Exhibit 99.1

Confidential material omitted and filed separately with the Securities
and Exchange Commission. Asterisks denote such omissions.

SPONSORED RESEARCH AND COLLABORATION AGREEMENT

by and between

THE J. DAVID GLADSTONE INSTITUTES

and

CAMBRIDGE NEUROSCIENCE PARTNERS, INC.

dated as of December 23, 1996

TABLE OF CONTENTS

1. DEFINITIONS.................................................... 1

2. INVESTIGATORS.................................................. 2
2.1. Principal Investigator................................... 2
2.2. Co-Investigator.......................................... 2

3. RESEARCH PROGRAM............................................... 2
3.1. General.................................................. 2
3.2. Records.................................................. 2
3.3. Consultation and Access.................................. 3

4. FUNDING AND RECORDS............................................ 3
4.1. Funding.................................................. 3
4.2. Funding Commitment....................................... 3
4.3. Equipment................................................ 3
4.4. Use of Funds............................................. 3

5. MEETINGS AND REPORTS........................................... 3
5.1. Meetings................................................. 3
5.2. Reports.................................................. 3

6. INTELLECTUAL PROPERTY RIGHTS................................... 4
6.1. Definitions.............................................. 4
6.2. Ownership of New Inventions.............................. 4
6.3. Disclosure of New Inventions in the Field................ 5
6.4. New Inventions Outside the Field......................... 5
6.5. Responsibility for Patent Filing and Prosecution......... 6
6.6. Research Results and Program Materials; Reserved Rights.. 7
6.7. Right to Fund Research Regarding New Opportunities....... 7
6.8. Invention Know-How....................................... 7
6.9. Warranties Regarding the Invention....................... 8
6.10. No Other Rights.......................................... 8

7. PUBLICATION AND CONFIDENTIALITY................................ 8
7.1. Publication Rights....................................... 8
7.2. Limitations on Publication............................... 8
7.3. Confidentiality.......................................... 9

8. TERM AND TERMINATION........................................... 10
8.1. Term..................................................... 10
8.2. Termination for Breach................................... 10
8.3. Effect of Termination.................................... 10
8.4. Survival................................................. 11

9. INDEMNIFICATION................................................ 11
9.1. Indemnification by CNPI.................................. 11
9.2. Indemnification by GLADSTONE............................. 12
9.3. Procedure................................................ 12

10. GENERAL PROVISIONS............................................. 12
10.1. Arbitration.............................................. 12
10.2. Governing Law............................................ 13
10.3. Independent Contractors.................................. 13
10.4. Parties Bound............................................ 13
10.5. Entire Agreement......................................... 13
10.6. Further Assurances....................................... 13
10.7. Right to Develop Independently........................... 13
10.8. Notices.................................................. 13
10.9. Use of Names............................................. 14
10.10. No Oral Modification............................... 14
10.11. Waiver............................................. 14
10.12. Headings........................................... 15
10.13. Severability....................................... 15
10.14. Counterparts....................................... 15
10.15. Force Majeure...................................... 15

SPONSORED RESEARCH AND COLLABORATION AGREEMENT

THIS SPONSORED RESEARCH AND COLLABORATION AGREEMENT ("Agreement"),
effective as of December 23, 1996 (the "Effective Date"), is made and entered
into by and between Cambridge NeuroScience Partners, Inc. ("CNPI"), a Delaware
corporation with its principal offices at One Kendall Square, Building 700,
Cambridge, MA 02139, and The J. David Gladstone Institutes ("GLADSTONE"), a
charitable trust with offices located at Irvine and San Francisco, California.

WHEREAS, CNPI desires to sponsor a program of research at GLADSTONE under
the direction of the Principal Investigator described in the Research Plan
attached as Exhibit A hereto;

WHEREAS, GLADSTONE desires to promote scientific inquiry and the public
benefit by conducting further research in the subject area of the Research Plan;

WHEREAS, CNPI desires to conduct collaborative research and to obtain
certain rights and licenses to inventions and technology arising out of or in
connection with such a program of research; and

WHEREAS, GLADSTONE is obligated to disclose and assign to the Regents of
the University of California ("The Regents"), a California corporation, in
accordance with an agreement dated June 8, 1977, as amended on March 27, 1984
and January 21, 1986 (the "Gladstone/Regents Agreement") all patentable rights
in intellectual property arising from research conducted by GLADSTONE
investigators under this Agreement, and, if The Regents elects to secure patent
protection for such rights, pursuant an Option Agreement of even date herewith
by and between The Regents and CNPI (the "Option Agreement"), The Regents is
obligated to grant CNPI exclusive rights to such patentable rights to the extent
provided in this Agreement and permitted under applicable law. If The Regents
elects not to secure patent protection for such rights and releases such rights
to the GLADSTONE investigator named as the inventor, the GLADSTONE investigator
is obligated, if requested by GLADSTONE, to assign such rights to GLADSTONE.

NOW, THEREFORE, in consideration of the promises and undertakings set
forth above and hereinafter, the parties hereto agree as follows:

1. DEFINITIONS

1.1. "Field" shall mean the "Field of Use" as that term is defined in the
Option Agreement.

1.2. "Party" shall mean GLADSTONE or CNPI except for purposes of Articles
6 and 8 and Section 10.1 hereof, wherein "Party" shall mean GLADSTONE/Regents
(as defined therein) or CNPI.

1.3. "Research Program" shall mean a program of research in the Field
mutually agreed to in writing by the Parties in accordance with the quarterly
meetings to be held pursuant to Section 5.1 hereof and as further described in
the Research Plan and Budget attached as Exhibit A hereto and made a part of
this Agreement.

2. INVESTIGATORS

2.1. PRINCIPAL INVESTIGATOR. For the purpose of this Agreement and
pursuant to GLADSTONE policy, Dr. Robert W. Mahley is designated the Principal
Investigator (the "Principal Investigator") who shall be responsible for the
administration, direction and content of the Research Program, including
budgeting and revisions to the budget reasonably necessary to accomplish the
Research Program, subject to the approval of CNPI, which approval shall not be
unreasonably withheld or delayed. Should the Principal Investigator leave
GLADSTONE or otherwise become unavailable during the term of this Agreement,
GLADSTONE may nominate a replacement, subject to the approval of CNPI. If CNPI
does not accept the replacement, the Research Program and budget may be modified
to reflect a reduced scope of work or terminated on thirty (30) days' prior
written notice at the option of CNPI in its sole discretion. CNPI hereby agrees
that Dr. Karl H. Weisgraber is an acceptable replacement.

2.2. CO-INVESTIGATOR. CNPI agrees to assign Dr. Robert N. McBurney (the
"Co-Principal Investigator") to direct CNPI's participation in the Research
Program. CNPI reserves the right to substitute a new Co-Principal Investigator
at any time without the prior approval of GLADSTONE.

3. RESEARCH PROGRAM

3.1. GENERAL. Principal Investigator will use his best efforts to conduct
the Research Program. The Research Program shall be under the direction of
Principal Investigator and shall be conducted at GLADSTONE. Modifications to the
Research Program may be made from time to time, as mutually agreed upon in
writing by GLADSTONE and CNPI.

3.2. RECORDS. The Principal Investigator and other personnel at GLADSTONE
assisting the Principal Investigator in the Research Program will keep accurate
scientific records relating to the Research Program and will make such records
available to CNPI during normal business hours upon reasonable notice. It is
understood that such records shall include detailed, witnessed laboratory
notebooks sufficient to document any patentable inventions made in the course of
the Research Program. Upon request by CNPI, and at its expense, the Principal
Investigator agrees promptly to provide copies of all such materials to CNPI. It
is understood by the Parties that CNPI owns its own records and laboratory
notebooks as well as those of the Co-Principal Investigator and GLADSTONE owns
the Principal Investigator's records and laboratory notebooks and the data
contained therein.

3.3. CONSULTATION AND ACCESS. The Co-Principal Investigator and/or his
designees may consult informally with the Principal Investigator, both in person
and by telephone, regarding performance of the Research Program. The
Co-Principal Investigator and/or his designees shall have reasonable access to
the GLADSTONE facilities where the Research Program is being conducted at times
convenient to GLADSTONE and after reasonable notice.

4. FUNDING AND RECORDS

4.1. FUNDING. As consideration for conducting the Research Program, CNPI
agrees to fund Principal Investigator's activities under the Research Program.
The level of funding as set forth in the budget attached hereto as Exhibit A
(the "Budget") shall be: One Million Two Hundred and Fifty Thousand Dollars
($1,250,000.00) in the first year; a minimum of One Million Two Hundred and
Fifty Thousand Dollars ($1,250,000.00) in the second year; and a minimum of One
Million Two Hundred and Fifty Thousand Dollars ($1,250,000.00) in the third
year. All funds shall be paid on a semi-annual basis, in advance.

4.2. FUNDING COMMITMENT. Unless this Agreement is earlier terminated
pursuant to Article 8 hereof, CNPI agrees to provide the total minimum amount of
funding for the three years of the Research Program as set forth in Section 4.1
above.

4.3. EQUIPMENT. Title to supplies or equipment purchased under the
Research Program shall vest in GLADSTONE.

4.4. USE OF FUNDS. GLADSTONE shall monitor expenditures in accordance with
its policies to ensure that the funds provided by CNPI are properly spent in the
performance of the Research Program.

5. MEETINGS AND REPORTS

5.1. MEETINGS. Joint scientific meetings between GLADSTONE and CNPI shall
occur quarterly during the term of this Agreement to discuss the results
generated under the Research Program and to consider modifications to the
Research Program based upon such results. Such meetings shall occur at CNPI or
GLADSTONE at such times as shall be determined by mutual agreement of GLADSTONE
and CNPI, at CNPI's expense, and shall be attended by Principal Investigator and
designated members of the GLADSTONE research group, and representatives of CNPI.

5.2. REPORTS. GLADSTONE shall promptly disclose data and information
obtained under the Research Program in written quarterly reports to CNPI.

6. INTELLECTUAL PROPERTY RIGHTS

6.1. Definitions.
-----------

(a) "Materials" shall mean any tangible biological, chemical or
physical materials.

(b) "New Invention" shall mean any potentially patentable invention
arising from the Research Program which is (i) conceived during the term of this
Agreement by employees or agents of GLADSTONE or by employees or agents of both
GLADSTONE and CNPI jointly and (ii) constructively or actually reduced to
practice during the term of this Agreement.

(c) "New Opportunity" shall mean any potentially patentable
invention arising from the Research Program other than New Inventions which is
conceived during the term of this Agreement by employees or agents of GLADSTONE
but which is not reduced to practice, either actually or constructively, during
the term of this Agreement.

(d) "Option/License Agreement" shall mean the Option Agreement and
any License Agreement (as it may be amended from time to time) resulting from
the exercise of the Option (as defined in the Option Agreement).

(e) "Program Materials" shall mean Materials that are discovered or
developed in the performance of the Research Program.

(f) "Research Results" shall mean all data, test results, laboratory
notes, techniques, know-how, and any other research results that are obtained in
the performance of the Research Program. The term "Research Results" shall not
include any Program Materials, patentable inventions, claims of copyright or
other intellectual property based on Research Results.

6.2. OWNERSHIP OF NEW INVENTIONS. All rights to New Inventions made
solely by GLADSTONE's employees and agents and arising from research conducted
under this Agreement shall belong to GLADSTONE, subject to the rights of The
Regents pursuant to the GLADSTONE/Regents Agreement (GLADSTONE and The Regents
are hereinafter referred to as "GLADSTONE/Regents"). CNPI shall cause its
employees and agents to assign all rights to New Inventions to CNPI. All rights
to New Inventions made jointly by GLADSTONE's employees or agents with one or
more employees or agents of CNPI and arising from research conducted under this
Agreement shall belong jointly to GLADSTONE/Regents and CNPI. CNPI shall be
granted rights under the Option/License Agreement to GLADSTONE's and The
Regents' interest in New Inventions in the Field in accordance with the terms
thereof and CNPI shall be granted rights under The Regents' interest in New
Inventions outside the Field in accordance with Section 6.4 below. The Regents
agrees to assert rights to the Invention (as defined in the Option/License
Agreement) and New Inventions both in and outside of the Field.

6.3. DISCLOSURE OF NEW INVENTIONS IN THE FIELD. Each Party shall promptly
disclose to the other Party any New Inventions in the Field arising under this
Agreement. The Party to whom such New Invention is disclosed agrees to hold such
disclosure on a confidential basis. The rights of CNPI to license New Inventions
in the Field are governed by the Option/License Agreement.

6.4. New Inventions Outside the Field.
--------------------------------

(a) GLADSTONE/Regents shall promptly disclose to CNPI any New
Inventions outside the Field arising under this Agreement. The Party to whom
such New Invention is disclosed agrees to hold such disclosure on a confidential
basis.

(b) To the extent that GLADSTONE and The Regents have the legal
right to do so, CNPI shall be entitled to an exclusive license to GLADSTONE's
and Regents' interest in each New Invention outside the Field on terms to be
negotiated in good faith between the Parties as set forth herein. CNPI agrees to
notify GLADSTONE/Regents in writing within ninety (90) days of disclosure of the
applicable New Invention outside the Field as to whether or not it wishes to
negotiate a license to such New Invention. Upon CNPI's affirmative election to
negotiate a license, GLADSTONE/Regents agree to negotiate in good faith with
CNPI for a period of one hundred and eighty (180) days to conclude, at CNPI's
option, either a license or option agreement for such New Invention. Such
license or option agreement shall include reasonable terms typically found in
licensing agreements and provide for diligent development of the New Invention
and CNPI's obligation to reimburse GLADSTONE/Regents for patent expenses
incurred by GLADSTONE/Regents with respect to such New Invention up to and
including the effective date of such license or option agreement. If, at the end
of such one hundred and eighty (180) day period, CNPI and GLADSTONE/Regents are
unable to agree on terms for the license or option agreement, then, unless the
Parties agree to extend the negotiation period, CNPI shall promptly deliver to
GLADSTONE/Regents a final proposal detailing the terms on which it would enter
into such an agreement (the "Final Proposal"). GLADSTONE/Regents shall have
thirty (30) days from receipt of the Final Proposal to notify CNPI of its
willingness to enter into an agreement on such terms. If GLADSTONE/Regents does
not so notify CNPI, then GLADSTONE/Regents shall be free to dispose of the
relevant New Invention in accordance with GLADSTONE/Regents' policy; provided,
however, that, for a period of two (2) years from the expiration of such thirty
(30) day period, if GLADSTONE/Regents proposes to enter into any such
arrangement with a third party on the terms set forth in the Final Proposal or
on terms more favorable to the third party than the terms contained in the Final
Proposal, then (i) GLADSTONE/Regents shall deliver to CNPI a notice specifying
such terms (an "Offer Notice"), (ii) CNPI shall have fifteen (15) days from
receipt of the Offer Notice to either waive its first refusal right or notify
GLADSTONE/Regents of its desire to negotiate in good faith a definitive
agreement reflecting such terms (the "Acceptance Notice") and (iii) if, at the
end of thirty (30) days from the Acceptance Notice, CNPI and GLADSTONE/Regents
fail to enter into a definitive agreement reflecting such terms, then the
parties shall submit any disputed issues regarding such agreement to binding
arbitration pursuant to Section 10.1 hereof. If CNPI waives its first refusal
right with respect to the terms set forth in the Offer Notice or fails to
deliver to GLADSTONE/Regents an Acceptance Notice within the requisite fifteen
(15) day period, then GLADSTONE/Regents shall be free to enter into an
arrangement for the relevant New Invention with a third party, the terms of such
arrangement

to be no more favorable to the third party than those set forth in the Offer
Notice if entered into during the aforementioned two (2) year period.

(c) If CNPI elects not to secure a license, then rights to such New
Invention may be disposed of by GLADSTONE/Regents with no further obligation to
CNPI.

6.5. Responsibility for Patent Filing and Prosecution.
-------------------------------------------------

(a) GLADSTONE/Regents shall control the preparation, filing and
prosecution of patent applications that are owned solely by GLADSTONE/Regents
and filed by GLADSTONE/Regents in connection with New Inventions in the Field as
provided in the Option/License Agreement.

(b) In the case of patent applications owned solely by
GLADSTONE/Regents and filed by GLADSTONE/Regents in connection with New
Inventions outside the Field, GLADSTONE/Regents shall provide CNPI in a timely
manner with copies of all patent applications filed by GLADSTONE/Regents in
connection therewith that may be or have been licensed to CNPI pursuant to this
Article 6 and/or the Option/License Agreement, as well as those documents
involved in the prosecution thereof, so that CNPI shall have an opportunity to
provide comment on any such applications and documents. Unless CNPI either (a)
notifies GLADSTONE/Regents pursuant to Section 6.4(b) that it does not wish to
negotiate a license to a New Invention or (b) fails, within the ninety (90)-day
period set forth in the said sentence, to notify GLADSTONE/Regents that it
wishes to negotiate such a license, CNPI shall bear the expenses associated with
the filing and prosecution of patent applications covering New Inventions
outside the Field. GLADSTONE/Regents will not abandon any such application
without the consent of CNPI for so long as CNPI agrees to pay for the expenses
thereof. In the event that GLADSTONE/Regents elects to abandon any patent
application with CAMBRIDGE NuCo's consent, CNPI may, in its sole discretion,
elect to take title to such patent application and continue prosecution of such
application, in which event GLADSTONE/Regents agrees to assign all of its rights
thereto to CNPI.

(c) CNPI shall control the preparation, filing, prosecution and
maintenance of patent applications that are jointly owned by CNPI and
GLADSTONE/Regents. Such applications shall be prepared, filed and prosecuted by
patent counsel reasonably acceptable to GLADSTONE/Regents. The Principal
Investigator and GLADSTONE/Regents shall cooperate fully with and provide
assistance to CNPI (or if the parties agree to have GLADSTONE/Regents exercise
control, CNPI shall cooperate fully with and provide assistance to
GLADSTONE/Regents) in connection with the preparation, filing, prosecution and
maintenance of such jointly-owned patent applications, including, without
limitation, execution of all documents and performance of all acts reasonably
necessary to file and prosecute such patent applications and maintain, enforce
and defend such patents. Each of CNPI and GLADSTONE/Regents shall provide the
other in a timely manner with copies of all jointly-owned patent applications
filed by each pursuant to Article 6, as well as those documents involved in the
prosecution thereof, so that the other shall have an opportunity to provide
comment on any such applications and documents. CNPI shall bear the expenses
associated with the filing and prosecution of such jointly-owned patent
applications. Neither Party shall abandon any such application without thirty
(30) days notice to the other.

6.6. Research Results and Program Materials; Reserved Rights.
-------------------------------------------------------

(a) CNPI shall have the unrestricted royalty-free right to use
Research Results for any purpose; provided, however, that CNPI shall not use
Research Results for commercial purposes unless it first obtains a commercial
license thereto if such use would infringe any claim of a patent application or
an issued patent as to which CNPI has not theretofore obtained a license for any
reason pursuant to the Option/License Agreement or Section 6.4(b) hereof. CNPI
shall have the right to use Program Materials for internal research programs. In
the event that (i) CNPI desires to obtain a commercial license to any Program
Materials that are not patentable or (ii) GLADSTONE/Regents determines that it
desires to grant a commercial license for any such Program Materials, CNPI
shall, in either case, have a right of first negotiation with respect to such a
license and the Parties shall negotiate such a license in good faith in
accordance with the procedures set forth in Section 6.4(b) hereof.
GLADSTONE/Regents shall have the unrestricted right to use the Research Results
for any purpose, subject to Section 7.2 hereof.

(b) GLADSTONE/Regents reserves the right to use any Program
Materials free of charge for its own research and educational purposes only.
GLADSTONE further retains the right to distribute any Program Material to others
engaged in non-commercial research, free of charge, under a written Gladstone
Material Transfer Agreement which provides that use shall be restricted to
non-commercial research. Prior to any transfer of Program Materials pursuant to
the preceding sentence, GLADSTONE/Regents shall cause any investigator and/or
institution to whom Program Materials are provided to enter into an agreement
setting forth publications procedures substantially similar to those set forth
in Sections 7.1 and 7.2 hereof providing CNPI with the right to review and
comment on publications to be made by such investigator and/or institution and
to remove any Confidential Information of CNPI. The Principal Investigator shall
provide CNPI with a list for its records of the investigators and institutions
to whom Program Materials have been provided as described under this Section
6.6(b) and shall keep the list current.

6.7. RIGHT TO FUND RESEARCH REGARDING NEW OPPORTUNITIES. At least sixty
(60) days prior to expiration or termination (except by GLADSTONE/Regents under
Section 8.2) of this Agreement, the Principal Investigator will disclose each
New Opportunity to CNPI in confidence and propose a program of research to
actually reduce such New Opportunity to practice. CNPI shall have the first
right to fund such additional research, such right to be exercised by written
notice to GLADSTONE/Regents within forty-five (45) days of disclosure of such
New Opportunity and program. Thereafter, the parties will promptly enter into a
Sponsored Research Agreement covering such research. Promptly following the
expiration or termination (except by GLADSTONE/Regents under Section 8.2) of
this Agreement, GLADSTONE/Regents will disclose any New Opportunities which
arose during the period since the original disclosure of New Opportunities, and
CNPI will have a first right to fund research to actually reduce such New
Opportunity to practice as set forth above. CNPI's rights under this Section 6.7
shall apply even if GLADSTONE/Regents constructively reduces a New Opportunity
to practice by filing a patent application prior to the expiration of the (45)
day period described above.

6.8. INVENTION KNOW-HOW. GLADSTONE/Regents agrees to provide CAMBRIDGE
NuCo with reasonable access to any technical information, experimental data
and/or tangible

Confidential material omitted and filed separately with the Securities and
Exchange Commission. Asterisks denote such omissions.

research materials relating to the Invention (as defined in the Option
Agreement) for the purpose of evaluating its interest in exercising its Option
under the Option Agreement.

6.9. WARRANTIES REGARDING THE INVENTION. GLADSTONE warrants that Dr.
Robert W. Mahley has not published or publicly presented any of the data or
research results contained in U.S. Patent Applications Serial *********** and
covering the Invention as defined in the Option Agreement.

6.10. NO OTHER RIGHTS. Nothing contained in this Agreement shall be deemed
to grant either directly or by implication, estoppel, or otherwise any license
under any patents, patent applications, or other proprietary interests to any
other invention, discovery, or improvement of any Party.

7. PUBLICATION AND CONFIDENTIALITY

7.1. Publication Rights.
------------------

(a) Subject to the rights granted to CNPI pursuant to this
Agreement, including without limitation Section 7.2, the Principal Investigator
shall have the right to publish or otherwise disclose all technical reports,
information and/or data developed by the Principal Investigator under this
Agreement. In connection with any publication or disclosure by the Principal
Investigator during the term of this Agreement or after of such reports,
information and/or data, CNPI may request that Principal Investigator include an
appropriate acknowledgement of CNPI's sponsorship of the Research Program in
such publication or disclosure.

7.2. Limitations on Publication.
--------------------------

(a) To avoid loss of patent rights as a result of premature public
disclosure of patentable information, the Principal Investigator and GLADSTONE
each agree to submit to CNPI, at least thirty (30) days prior to submission for
publication or disclosure, any and all materials intended for publication or
disclosure relating to technical reports, data, or information developed by the
Principal Investigator and/or other personnel at GLADSTONE assisting the
Principal Investigator under this Agreement. In the event CNPI believes
patentable subject matter is disclosed in such materials it shall, within
fifteen (15) days of its receipt thereof, notify GLADSTONE and publication or
disclosure will thereupon be withheld for a period of up to ninety (90) days
from the date of receipt by CNPI of the proposed publication or other disclosure
so that a patent application covering such invention may be prepared and filed
as provided in Section 6.3. Further, if CNPI believes that such materials
contain Confidential Information (as defined below) of CNPI, the Principal
Investigator and GLADSTONE agree to remove such Confidential Information from
the proposed publication or disclosure. Further, in the case of a publication
based on the results of x-ray crystallography, GLADSTONE agrees that the
three-dimensional coordinates of any target molecules will not be published
until such publication is required under the policy of the academic journal in
which the results were first published.

(b) CNPI agrees that, during the term of this Agreement and after,
CNPI will appropriately acknowledge the contributions of the Principal
Investigator and GLADSTONE in any publication or disclosure by CNPI of Research
Results and data based upon the Research Program. In addition, CNPI agrees to
provide the Principal Investigator a copy of any such publication or disclosure
in confidence for information purposes at least thirty (30) days before public
release of such publication or disclosure. The Principal Investigator shall have
the right to reasonably edit any such publications or disclosures which are
jointly authored by Principal Investigator. The foregoing shall not apply to
press releases of Cambridge NeuroScience, Inc. ("CNSI") and/or CNPI issued in
the ordinary course of business or to reports filed by CNSI and/or CNPI with the
National Association of Securities Dealers, the Securities and Exchange
Commission or any other governmental agency in accordance with applicable laws
or regulations.

7.3. CONFIDENTIALITY. Either Party, from time to time, in connection with
the Research Program, may disclose Confidential Information to the other Party.
For purposes of this Agreement, "Confidential Information" shall mean
confidential and proprietary information and materials that are designated as
confidential in writing by the providing Party, whether by letter or by use of
an appropriate stamp or legend, prior to or at the same time any such
information or materials are disclosed. Notwithstanding the foregoing to the
contrary, materials and other information which are orally, visually or
electronically disclosed, or are disclosed in writing without an appropriate
letter, stamp, or legend, shall constitute Confidential Information if the
providing Party, within thirty (30) days after such disclosure, delivers to the
other Party a written document or documents describing the materials and
identifying the Confidential Information. The Parties agree, to the extent
permitted by law, that Confidential Information shall remain the property of the
providing Party. Each of the Parties further agree to use its best efforts to
insure that Confidential Information shall not be disclosed, divulged or
otherwise communicated to third parties or used for any purposes other than to
conduct the Research Program, provided that the obligations under this Section
7.3 shall not apply to information that:

(a) is in possession of the recipient at the time of disclosure
thereof a demonstrated by written records;

(b) is or later becomes part of the public domain through no
fault of the recipient;

(d) is developed independently by the recipient without use of
Confidential Information; or

(e) is required by law or regulation to be disclosed; provided,
however, that recipient has provided written notice to providing Party promptly
to enable the providing Party to seek a protective order or otherwise prevent
disclosure of such information.

Confidential material omitted and filed separately with the Securities and
Exchange Commission. Asterisks denote such omissions.

8. TERM AND TERMINATION

8.1. TERM. The term of this Agreement ("Term") shall commence on the
Effective Date and continue in full force for three (3) years from and after the
Effective Date, unless earlier terminated in accordance with Section 2.1 or this
Article 8. This Agreement may be renewed or extended by mutual written consent
of the Parties within thirty (30) days prior to expiration.

8.2. TERMINATION FOR BREACH. If either Party materially breaches any
material warranty, term or condition of this Agreement (including but not
limited to CNPI's failure to make any payments due and the failure of GLADSTONE
and/or the Principal Investigator to diligently perform its or his respective
obligations with respect to the Research Program in substantial accordance with
Exhibit A hereto) and fails to remedy such material breach within sixty (60)
days after receipt of notice in writing of such material breach from the other
Party, the non-breaching Party, at such Party's option and in addition to any
other remedies that such Party may have in law or in equity, may terminate this
Agreement by sending written notice of termination with immediate effect to the
other Party.

8.3. EFFECT OF TERMINATION. Termination of this Agreement shall not
affect the rights and obligations of the parties which accrued hereunder except
as provided under this Section 8.3.

(a) In the event that this Agreement is terminated for any reason,
GLADSTONE will proceed in an orderly fashion to terminate any outstanding
commitments and to stop the Research Program as soon as it is practicable to do
so. All documented costs reasonably incurred by GLADSTONE in connection with
such termination will be considered reimbursable costs, including costs incurred
prior to the notice of termination but which have not yet been reimbursed, and
commitments existing at the time the notice of termination is received which by
their terms cannot be canceled. This shall include all non-cancelable contracts
entered into and fellowships or postdoctoral associate appointments offered and
accepted prior to the effective date of termination. After termination, any
obligation of CNPI to GLADSTONE with respect to fellowships or postdoctoral
associate appointments shall end as soon as possible consistent with GLADSTONE
personnel policies and in no event later than ***************** from the date of
notice of termination. In no case will such reimbursement exceed the total
estimated projected cost of the Research Program, unless otherwise mutually
agreed to by the Parties. Termination of this Agreement shall not relieve CNPI
from the obligation to make any payments due and payable to GLADSTONE as of the
date of termination. GLADSTONE shall have the right to retain, in full, payments
received pursuant to Section 4.1 prior to the date of termination.

(b) In the event this Agreement is terminated by CNPI pursuant to
Sections 2.1 or 8.2 above,

(i) CNPI's exclusive option for an exclusive license under
the Option Agreement or additional exclusive licenses
under the License Agreement, as the case may be, shall
continue in full force and effect with respect to the
Invention (as defined therein) and any

New Inventions arising on or prior to the date on which
the Research Program is terminated pursuant to clause
(a) above, and the Option Agreement shall not be
terminated by The Regents except as provided in clause
(ii) below.

(ii) CNPI shall notify The Regents within six (6) months of
the date of termination of the Research Program pursuant
to clause (a) above whether CNPI is exercising its
option under the Option Agreement, such notice to be in
the form required by the Option Agreement. If CNPI
elects not to exercise its option under the Option
Agreement or fails to properly do so within the
aforementioned six (6) month period, then The Regents
may terminate the Option Agreement in accordance with
its terms. If CNPI properly exercises its option under
the Option agreement, then CNPI and The Regents shall
negotiate the License Agreement or amendment(s) thereto
(as the case may be) as provided in the Option/License
Agreement.

(iii) CNPI's right of first refusal under Section 6.4 hereof
shall continue in full force and effect (A) with respect
to any and all New Inventions arising prior to or on the
date on which the Research Program is terminated
pursuant to clause (a) of this Section 8.3 as to which
CNPI has elected (or has been deemed to have elected)
not to secure a license pursuant to Section 6.4 hereof
and (B) until the expiration of the applicable two (2)
year period with respect to each New Invention for which
a Final Proposal has been delivered.

(c) In the event this Agreement is terminated by GLADSTONE/Regents
pursuant to Section 8.2 above, CNPI's exclusive option for an exclusive license
under the Option Agreement, or for additional exclusive licenses under the
License Agreement, as the case may be, shall terminate, and the Option Agreement
shall terminate.

8.4. SURVIVAL. The following Sections and Articles of this Agreement
shall survive the expiration or termination for any reason of this Agreement:
Sections 3.2, 6.2, 6.4 (as provided in Section 8.3(b) above), 6.5, 6.6, 8.3 and
8.4 and Articles 7, 9 and 10.

9. INDEMNIFICATION

9.1. INDEMNIFICATION BY CNPI. CNPI agrees to defend, indemnify and hold
harmless GLADSTONE, its partners, its employees and or agents from and against
all complaints, causes of action, claims, losses, costs, damages, liabilities,
or expenses by reason of any liability sought to be imposed upon GLADSTONE
resulting from injuries to persons or damages to property, provided such
injuries to persons or damage to property are due or claimed to be due as a
result of acts or omissions of acts of CNPI, its officers, employees or agents.

9.2. INDEMNIFICATION BY GLADSTONE. GLADSTONE agrees to defend, indemnify
and hold harmless CNPI, its affiliates, officers, directors, employees and
agents from and against all complaints, causes of actions, claims, losses,
costs, damages, liabilities, or expenses by reason of any liability sought to be
imposed upon CNPI resulting from injuries to persons or damages to property,
provided such injuries to persons or damages to property are due or claimed to
be due as a result of acts or omission of acts of GLADSTONE, its partners,
employees or agents.

9.3. PROCEDURE. A Party or any of its Affiliates or their respective
employees or agents (the "Indemnitee") that intends to claim indemnification
under this Article 9 shall promptly notify the other Party (the "Indemnitor") of
any loss, claim, damage, liability, expenses, or action in respect of which the
Indemnitee intends to claim such indemnification, and the Indemnitor shall
assume the defense thereof with counsel mutually satisfactory to the Parties;
provided, however, that an Indemnitee shall have the right to retain its own
counsel, with the fees and expenses to be paid by the Indemnitor, if
representation of such Indemnitee by the counsel retained by the Indemnitor
would be inappropriate due to actual or potential differing interests between
such Indemnitee and any other party represented by such counsel in such
proceedings. The indemnity agreement in this Article 9 shall not apply to
amounts paid in settlement of any loss, claim, damage, liability or action if
such settlement is effected without the consent of the Indemnitor, which consent
shall not be withheld unreasonably. The failure to deliver notice to the
Indemnitor within a reasonable time after the commencement of any such action,
if materially prejudicial to its ability to defend such action, shall relieve
such Indemnitor of any liability to the Indemnitee under this Article 9, but the
omission so to deliver notice to the Indemnitor will not relieve it of any
liability that it may have to any Indemnitee otherwise than under this Article
9. The Indemnitee under this Article 9, its employees and agents, shall
cooperate fully with the Indemnitor and its legal representatives in the
investigation of any action, claim or liability covered by this indemnification.
In the event that each Party claims indemnity from the other and one Party is
finally held liable to indemnify the other, the Indemnitor shall additionally be
liable to pay the reasonable legal costs and attorneys' fees incurred by the
Indemnitee in establishing its claim for indemnity.

10. GENERAL PROVISIONS

10.1. ARBITRATION. If the Principal Investigator and the Co-Principal
Investigator can not resolve a dispute, any controversy or claim arising out of
or relating to any provision of this Agreement or any breach thereof, shall be
settled by arbitration conducted in California in accordance with the Commercial
Arbitration Rules of the American Arbitration Association. The arbitration panel
will be conducted before a single arbitrator with experience in the
biotechnology industry provided that both Parties are able to agree on the
identity of such single arbitrator. If the Parties cannot agree on a single
arbitrator, there will be three arbitrators, with each Party selecting one and
the two arbitrators so selected choosing a third. Judgment upon the award
rendered by the arbitrator(s) shall be binding on the Parties and may be entered
by either Party in any court or forum, state or federal, having jurisdiction.

10.2. GOVERNING LAW. This Agreement shall be governed by, construed, and
interpreted in accordance with the laws of the State of California, without
reference to principles of conflicts of laws.

10.3. INDEPENDENT CONTRACTORS. The relationship of CNPI and GLADSTONE
established by this Agreement is that of independent contractors, and nothing
contained in this Agreement shall be construed to (i) give any of the Parties
hereto the power to direct or control the day-to-day activities of another Party
hereto, (ii) constitute the Parties as partners, joint venturers, co-owners or
otherwise as participants in a joint or common undertaking or (iii) allow any of
the Parties hereto to create or assume any obligations on behalf of another
Party hereto for any purposes whatsoever.

10.4. PARTIES BOUND. This Agreement, including the indemnification
provisions, shall be binding upon and inure to the benefit of the Parties
hereto, their respective successors, assigns, legal representatives and heirs.
CNPI may assign or transfer CNPI's rights and obligations under this Agreement
to an affiliate of CNPI or a successor to all or substantially all of its assets
or business relating to this Agreement, whether by sale, merger, operation of
law or otherwise. This Agreement shall not otherwise be assignable by either
Party without the prior written consent of the other Party.

10.5. ENTIRE AGREEMENT. This Agreement and the Option/License Agreement
constitute the entire and only agreements between the parties relating to the
subject matter hereof, and all prior negotiations, representations, agreements
and understandings are superseded by this Agreement and the Option/License
Agreement.

10.6. FURTHER ASSURANCES. At any time or from time to time on and after
the Effective Date, the Principal Investigator and GLADSTONE shall at the
request of CNPI (i) deliver to CNPI such records, data or other documents
consistent with the provisions of this Agreement, (ii) execute, and deliver or
cause to be delivered, all such assignments, consents documents or further
instruments of transfer or licenses and (iii) take or cause to be taken all such
other actions, as CNPI may reasonably deem necessary or desirable in order for
CNPI to obtain the full benefits of this Agreement and the transactions
contemplated hereby.

10.7. RIGHT TO DEVELOP INDEPENDENTLY. Nothing in this Agreement will
impair CNPI's right to independently acquire, license, develop or have
developed, utilize or otherwise exploit similar information and technology
performing the same or similar functions as the information and technology
provided by the Principal Investigator and/or GLADSTONE. In addition, nothing in
this Agreement is intended to prohibit Principal Investigator from independently
collaborating with academic, non-commercial parties on the Research Program with
the prior written consent of CNPI. CNPI hereby acknowledges that the Principal
Investigator intends to enter into an agreement with Lawrence Livermore National
Laboratory to perform the crystallography work of the Research Program and
consents to such arrangement.

10.8. NOTICES. Except for the remittance of payments which are governed by
Section 4.1, any notice or other communication required or permitted under this
Agreement shall be in writing and will be deemed received, if delivered by
courier on a business day, on the day delivered, or five (5) days after mailing
if mailed by first-class, certified or registered mail,

postage prepaid, to the respective addresses given below or to such other
addresses as are designated by written notice:

If to GLADSTONE or the
Principal Investigator: The J. David Gladstone Institutes
P.O. Box 419100
San Francisco, CA 94141-9100
Attention: Dr. Robert W. Mahley
Executive Director

with a copy to: Richard Hille
J. David Gladstone Institutes
43 Corporate Park
Suite 102
Irvine, CA 92714

If to CNPI: CNPI
c/o Cambridge NeuroScience, Inc.
One Kendall Square
Building 700
Cambridge, MA 02139
Attention: Harry W. Wilcox

with a copy to: Palmer & Dodge LLP
One Beacon Street
Boston, MA 02108
Attention: F. Andrew Anderson, Esq.

10.9. USE OF NAMES. Neither Party will use the name of the other Party or
its employees in any advertisement, press release, or other publicity without
the prior written approval of the other Party, such approval not to be
unreasonably withheld or delayed, except as may be required by applicable
federal or state securities laws or regulations. CNPI understands that the
California Education Code section 92000 provides that the name "University of
California" is the property of the State of California and that no person shall
use that name in a manner prohibited by the said Section 92000 without the
permission of The Regents. Such permission may be granted by the Chancellor or
his designee. GLADSTONE shall have the right to acknowledge CNPI's support of
the research performed under this Agreement in scientific publications and other
scientific communications.

10.10. NO ORAL MODIFICATION. No change, modification, extension,
termination of this Agreement or of any provisions hereof shall be effective
unless assented to in writing by each of the Parties.

10.11. WAIVER. No waiver of any rights, shall be effective unless assented
to in writing by the Party to be charged and the waiver of any breach of default
shall not constitute a waiver of any other right hereunder or any subsequent
breach or default.

10.12. HEADINGS. The headings of the Sections and Articles of this
Agreement are intended for convenience of reference only and are not intended to
affect in any way the meaning or interpretation of this Agreement.

10.13. SEVERABILITY. In the event that any provision of this Agreement
becomes or is declared by a court of competent jurisdiction to be illegal,
unenforceable or void, this Agreement shall continue in full force and effect
without said provision; provided, that no such severability shall be effective
if the result of such action materially changes the economic benefit of this
Agreement to CNPI, or to the Principal Investigator or GLADSTONE.

10.14. COUNTERPARTS. This Agreement may be executed in counterparts, each
of which shall be deemed an original, but all of which together shall constitute
one and the same instrument.

10.15. FORCE MAJEURE. The parties to this Agreement shall be excused from
any performance required hereunder if such performance is rendered impossible or
unfeasible due to any catastrophes or other major events beyond their reasonable
control, including, without limitation, war, riot, and insurrection; laws,
proclamations, edicts, ordinances or regulations; strikes, lock-outs or other
serious labor disputes; and floods, fires, explosions, or other natural
disasters. When such events have abated, the Parties' respective obligations
hereunder shall resume.

IN WITNESS WHEREOF, each of the undersigned have caused this Agreement to
be executed by their duly authorized representatives.

CAMBRIDGE NEUROSCIENCE PARTNERS, INC.

By: /s/ R.N. McBurney Date
---------------------------------------- -------------------
Name: R.N. McBurney
---------------------------------------
(please print)

Title: President
-------------------------------------

THE J. DAVID GLADSTONE INSTITUTE

By: /s/ Richard S. Brawerman Date
---------------------------------------- -------------------
Richard S. Brawerman, Trustee

By: /s/ Albert A. Dorman Date
---------------------------------------- -------------------
Albert A. Dorman, Trustee

By: /s/ Richard D. Jones Date
---------------------------------------- -------------------
Richard D. Jones, Trustee

I have read and agree to the terms and conditions of this Agreement:

By: /s/ Dr. Robert W. Mahley Date
---------------------------------------- -------------------
Dr. Robert W. Mahley
Principal Investigator

CAMBRIDGE NEUROSCIENCE, INC. agrees to guarantee performance of CNPI's financial
obligations under Section 8.3(a) and Articles 4, 6 and 9 of this Agreement.

By:/s/ Elkan Gamzu Date
---------------------------------------- -------------------
Name: Elkan Gamzu
--------------------------------------
(please print)

Title: President and CEO
-------------------------------------

Confidential material ommitted and filed separately with the Securities and
Exchange Commisssion. Asterisks denote such ommissions.

Exhibit A
---------

GLADSTONE INSTITUTE OF CARDIOVASCULAR DISEASE
CAMBRIDGE NEUROSCIENCE PROPOSAL

This proposal represents an integrated approach for a drug discovery
program targeting populations that will likely include: Alzheimer's disease,
stroke, head trauma, central nervous system infections, and age-associated
cognitive decline. The proposal is based on the concept that apolipoprotein
(apo-)E plays a critical role in a final common pathway in neuronal
repair/remodeling (Figure 1). The proposed drug development program is based on
the following hypotheses that have resulted from the research of Gladstone
investigators.

************************************

- 1 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 2 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 3 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 4 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 5 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 6 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 7 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 8 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 9 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 10 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 11 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

************************************

- 12 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

***********************************

- 13 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

BUDGET

I. Scientific Staff
% effort
--------

Robert W. Mahley, M.D., Ph.D. *** Project Director
Karl H. Weisgraber, Ph.D. *** Co-investigator
Robert E. Pitas, Ph.D. *** Co-investigator
Lennart Mucke, M.D. *** Co-investigator

******
II. Support Staff
Supervisor % effort Salary
---------- -------- ------
Hassibullah Akeefe Mahley/Pitas **** *****
Research Associate
Manuel Buttini, Ph.D. Mucke **** *****
Postdoctoral Fellow
Francine Compagno Mucke **** *****
Research Associate
Mark Holm, M.D. Mahley/Pitas **** *****
Postdoctoral Fellow
Yvonne M. Newhouse Weisgraber **** *****
Senior Research Associate
Stephen J. Russell Weisgraber **** *****
Research Associate
Lubica Supekova, Ph.D. Mahley/Pitas **** *****
Postdoctoral Fellow
Anton Wyss-Coray, Ph.D. Mucke **** *****
Staff research Investigator
Xiao, Xu, M.D., Ph.D. Mucke **** *****
Postdoctoral Fellow
Postdoctoral Fellow, TBN Weisgraber **** *****
(X-ray crystallography)
Postdoctoral Fellow, TBN Pitas **** *****
(cell biology)
Postdoctoral Fellow, TBN Mucke **** *****
(transgenic models)

*****
III. Supplies

************************ *****
************************ *****
************************ *****
************************ *****
************************ *****
************************ *****

- 14 -

Confidential material ommitted and filed separately with the Securities
and Exchange Commisssion. Asterisks denote such ommissions.

*****
(Approximately 12 full-time staff assigned to this
program--supply budget represents about *******
per research associate/postdoctoral fellow/scientist)

IV. Animal Models

Animal purchases and per diem costs *****

V. X-ray Crystallography Support Servies
(Lawrence Livermore National Laboratory)

Personnel % effort
--------- --------
B.Rupp, Ph.D. **** *****
S. Parkin, Ph.D. **** *****
*****

Supplies *****
Organization facility charge *****
*****
Total direct cost *****
Indirect cost *****
Total *****

VI. Travel

Travel to research meetings with Cambridge NeuroScience scientists:
4 investigators x *** trips @ ****** each *****
Total Gladstone direct costs *****
Gladstone indirect costs (benefits, overhead) *****
TOTAL *****

Budget for Year 02

Year 01 plus **** adjustment for inflation *****

Budget for Year 03

Year 02 plus **** adjustment for inflation *****

* Notwithstanding the above totals, NCPI's funding obligations are limited to
the amounts set forth in Section 4.1 of the Agreement.

- 15 -

FF
Principal Investigator/Program Director (Last, first, middle): Mahley, Robert W.
- --------------------------------------------------------------------------------

BIOGRAPHICAL SKETCH

Provide the following information for the key personnel in the order listed on
Form Page 2. Photocopy this page or follow this format for each person.
- --------------------------------------------------------------------------------
NAME POSITION TITLE
Robert W. Mahley Director
- --------------------------------------------------------------------------------
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional
education, such as nursing, and include postdoctoral training.)
- --------------------------------------------------------------------------------
DEGREE
INSTITUTION AND LOCATION (if applicable) YEAR(S) FIELD OF STUDY
- --------------------------------------------------------------------------------
Maryville College, Maryville, TN B.S. 1963
Vanderbilt University, Nashville, TN Ph.D. 1968 Pathology/Anatomy
Vanderbilt University, Nashville, TN M.D. 1970

- --------------------------------------------------------------------------------

RESEARCH AND PROFESSIONAL EXPERIENCE: Concluding with present position, list,
in chronological order, previous employment, experience, and honors. Include
present membership on any Federal Government public advisory committee. List, in
chronological order, the titles, all authors, and complete references to all
publications during the past three years and to representative earlier
publications pertinent to this application. If the list of publications in the
last three years exceeds two pages, select the most pertinent publications. DO
NOT EXCEED TWO PAGES.
EMPLOYMENT AND EXPERIENCE
1963-1964 Instructor of Biology, Maryville College, Maryville, TN
1964-1970 Combined M.D.-Ph.D. program at Vanderbilt University,
Nashville, TN
1970-1971 Internship, Pathology, Vanderbilt University, Nashville, TN
1971-1975 Staff, National Heart, Lung and Blood Institute, NIH,
Bethesda, MD
1975-1979 Head, Comparative Atherosclerosis and Arterial Metabolism
Section, Laboratory of Experimental Atherosclerosis, National
Heart, Lung and Blood Institute, NIH, Bethesda, MD
1979-Present Director, Gladstone Institute of Cardiovascular Disease;
Senior Staff Member, Cardiovascular Research Institute, and
Professor of Pathology and Medicine, University of California,
San Francisco, CA
1992-Present President, The J. David Gladstone Institutes
PROFESSIONAL SOCIETIES AND HONORS
Association of American Physicians; American Society for Clinical Investigation;
American Society of Biological Chemistry; International Academy of Pathology;
American Heart Association (AHA); Merrill Award in Experimental Pathology;
Bordon Award for Basic Medical Research; Vivian B. Allen Medical Scholarship;
Pfizer Traveling Fellows; Heinrich Wieland Prize; Chairman, Program Committee of
Council on Arteriosclerosis (AHA); Chairman, Gordan Conference on Lipid
Metabolism; Editorial Boards: Journal of Lipid Research, Journal of Clinical
Investigation, and Journal of Clinical Investigation; Chairman, Gordon
Conference on Arteriosclerosis; George Lyman Duff Memorial Lectureship (AHA
award); National Research Committee (AHA); CIBA-GEIGY Drew Award in Biomedical
Research; Metropolitan Life Foundation Award for Medical Research; Honorary
Degree of Doctor of Medicine, University of Goteborg, Goteborg, Sweden; National
Cholesterol Education Program DeWitt S. Goodman Award for Basic Science
Achievement.
PUBLICATIONS (selected recent publications)
1. Mahley, R.W. (1988 Apolipoprotein E: Cholesterol transport protein with
expanding role in cell biology. Science 240: 622-630.
2. Boyles, J.K., Zoellner, C.D., Anderson, L.J., Kosik, L.M., Pitas, R.E.,
Weisgraber, K.H., Hui, D.Y., Mahley, R.W., Gebicke-Haerter, P.J., Ignatius,
M.J., and Shooter, E.M. (1989) A role for apolipoprotein E, apolipoprotein
A-I, and low density lipoprotein receptors in cholesterol transport during
regeneration and remyelination of the rat sciatic nerve. J. Clin. Invest.
83: 1015-1031.
3. Mahley, R.W., Hui, D.Y., Innerarity, T.L., and Beisiegel U. (1989)
Chylomicron remnant metabolism. Role of hepatic lipoprotein receptors in
mediating uptake. Arteriosclerosis 9: I-14--I-8.
4. Hussain, M.M., Mahley, R.W., Boyles, J.K., Fainaru, M., BRECHT, W.J., and
Lindquist, P. (1989) Chylomicronchyomicron remnant clearance by liver and
bone marrow in rabbits. Factors that modify tissue-specific uptake. J.
Biol. Chem. 264: 9571--9582.
5. Hussain, M.M., Mahley, R.W., Boyles, J.K., Lindquist, P.A., Brecht, W.J.,
and Innerarity, T.L. (1989) Chylomicron metabolism. Chylomicron uptake by
bone marrow in different animal species. J. Biol. Chem. 264: 17931--17938.

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PHS 398 (Rev. 5/95) (Form Page 6) Page 16 FF
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Do NOT use suffixes such as 3a, 3b.

Principal Investigator/Program Director (Last, first, middle): Mahley, Robert W.
- --------------------------------------------------------------------------------

6. Mahley, R.W., Weisgraber, K.H., Hussain, M.M., Greenman, B., Fisher, M.,
Vogel, T., and Gorecki, M. (1989) Intravenous infusion of apolipoprotein E
accelerates clearance of plasma lipoproteins in rabbits. J. Clin. Invest.
83: 2125--2130.
7. Weisgraber, K.H., Mahley, R.W., Kowal, R.C., Herz, J., Goldstein, J.L., and
Brown, M.S. (1990) Apolipoprotein C-I modulates the interaction of
apolipoprotein E with (beta)-migrating very low density lipoproteins
((beta)-VLDL) and inhibits binding of (beta)-VLDL to low density
lipoprotein receptor-related protein. J. Biol. Chem. 265: 22453--22459.
8. Innerarity, T.L., Mahley, R.W., Weisgraber, K.H., Bersot, T.P., Krauss,
R.M., Vega, G.L., Grundy, S.M., Friedl, W., Davignon, J., and McCarthy,
B.J. (1990) Familial defective apolipoprotein B100: A mutation of
apolipoprotein B that causes hypercholesterolemia. J. Lipid Res. 31:
1337--1349.
9. Mahley, R.W., Weisgraber, K.H., Innerarity, T.L., and Rall, S.C., Jr.
(1991) Genetic defects in lipoprotein metabolism. Elevation of atherogenic
lipoproteins caused by impaired catabolism. J. Am. Med. Assoc. 265: 78--83.
10. Hussain, M.M., Maxfield, F.R., Mas-Oliva, J., Tabas, I., JI, Z.-S.,
Innerarity, T.L., and Mahley, R.W. (1991) Clearance of chylomicron remnants
by the low density lipoprotein receptor-related
protein/[alpha]2-macroglobulin receptor. J. Biol. Chem. 266: 13936--13940.
11. Wilson, C., Wardell, M.R., Weisgraber, K.H., Mahley, R.W., and Agard, D.A.
(1991) Three-dimensional structure of the LDL receptor-binding domain of
human apolipoprotein E. Science 252: 1817--1822.
12. Handelmann, G.E., Boyles, J.K., Weisgraber, K.H., Mahley, R.W., and Pitas,
R.E. (1992) Effects of apolipoprotein E, (beta)-very low density
lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal
root ganglion neurons in vitro. J. Lipid Res. 33: 1677--1688.
13. Ji, Z-S., Brecht, W.J., Miranda, R.D., Hussain, M.M., Innerarity, T.L., and
Mahley, R.W. (1993) Role of heparan sulfate proteoglycans in the binding
and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured
cells. J. Biol. Chem. 268: 10160--10167.
14. Ji, Z.-S., Fazio, S., Lee, Y.-L., and Mahley, R.W. (1994) Secretion-capture
role for apolipoprotein E in remnant lipoprotein metabolism involving cell
surface heparan sulfate proteoglycans. J. Biol. Chem. 269: 2764--2772.
15. Ji, Z-S., Fazio, S., and Mahley, R.W. (1994) Variable heparan sulfate
proteoglycan binding of apolipoprotein E variants may modulate the
expression of type III hyperlipoproteinemia. J. Biol. Chem. 269:
13421--13428.
16. Nathan, B.P., Bellosta, S., Sanan, D.A., Weisgraber, K.H., Mahley, R.W.,
and Pitas, R.E. (1994) Differential effects of apolipoprotein E3 and E4 on
neuronal growth in vivo. Science 264: 850--852.
17. Dong, L.-M., Wilson, C., Wardell, M.R., Simmons, T., Mahley, R.W.,
Weisgraber, K.H., and Agard, D.A. (1994) Human apolipoprotein E. Role of
arginine 61 in mediating the lipoprotein preferences of the E3 and E4
isoforms. J. Biol. Chem. 269: 22358--22365.
18. Ji, Z.-S., Sanan, D.A., and Mahley, R.W. (1995) Intravenous heparinase
inhibits remnant lipoprotein clearance from the plasma and uptake by the
liver: In vivo role of heparan sulfate proteoglycans. J. Lipid Res. 36:
583--592.
19. Mahley, R.W., Nathan, B.P., Bellosta, S., and Pitas, R.E. (1995)
Apolipoprotein E: Impact of cytoskeletal stability in neurons and the
relationship to -- Alzheimer's disease. Curr. Opin. Lipidol. 6: 86--91.
20. Bellosta, S., Mahley, R.W., Sanan, D.A., Murata, J., Newland, D.L., Taylor,
J.M., and Pitas, R.E. (1995) Macrophage-specific expression of human
apolipoprotein E reduces atherosclerosis in hypercholesterolemic
apolipoprotein E-null mice. J. Clin. Invest. 96: 2170--2179.
21. Nathan, B.P., Chang, K.-C., Bellosta, S., Brisch, E., Ge, N., Mahley, R.W.,
and Pitas, R.E. (1995) The inhibitory effect of apolipoprotein E4 on
neurite outgrowth is associated with microtubule depolymerization. J. Biol.
Chem. 270: 19791--19799.
22. Holtzman, D.M., Pitas, R.E., Kilbridge, J., Nathan, B., Mahley, R.W., Bu,
G., and Schwartz, A.L. (1995) Low density lipoprotein receptor-related
protein mediates apolipoprotein E-dependent neurite outgrowth in a central
nervous system-derived neuronal cell line. Proc. Natl. Acad. Sci. USA 92:
9480--9484.
23. Bellosta, S., Nathan, B.P., Orth, M., Dong, L-M., Mahley, R.W., and Pitas,
R.E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in
mouse neuroblastoma cells produces differential effects on neurite
outgrowth. J. Biol. Chem. 270: 27063--27071.
24. Mahley, R.W., Nathan, B.P., and Pitas, R.E. Apolipoprotein E: Structure,
function, and possible roles in Alzheimer's disease. Ann. N.Y. Acad. Sci.
In press.

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PHS 398 (Rev. 5/95) Page 17
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suffixes such as 3a, 3b.

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Principal Investigator/Program Director (Last, first, middle): Mahley, Robert W.
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BIOGRAPHICAL SKETCH

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NAME POSITION TITLE
Karl H. Weisgraber Senior Scientist, Associate Director

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EDUCATION/TRAINING (Begin with baccalaureate or other initial professional
education, such as nursing, and include postdoctoral training.)
- --------------------------------------------------------------------------------
DEGREE
INSTITUTION AND LOCATION (if applicable) YEAR(S) FIELD OF STUDY
- --------------------------------------------------------------------------------
University of Connecticut, Storrs, CT B.A. 1964 Chemistry
University of Connecticut, Storrs, CT Ph.D. 1969 Organic
Chemistry

- --------------------------------------------------------------------------------

RESEARCH AND PROFESSIONAL EXPERIENCE: Concluding with present position, list, in
chronological order, previous employment, experience, and honors. Include
present membership on any Federal Government public advisory committee. List, in
chronological order, the titles, all authors, and complete references to all
publications during the past three years and to representative earlier
publications pertinent to this application. If the list of publications in the
last three years exceeds two pages, select the most pertinent publications. DO
NOT EXCEED TWO PAGES.
EMPLOYMENT AND EXPERIENCE
1969-1970 Staff Fellow, National Institute of Arthritis, Metabolism and
Digestive Diseases, Bethesda, MD
1970-1971 National Research Council Postdoctoral Research Associate,
Agricultural Research Service USDA, Pasadena, CA
1972 Principal Scientist, Meloy Laboratories, Springfield, VA
1972-1976 Senior Staff Fellow, National Heart and Lung Institute, Bethesda,
MD
1976-1979 Expert, National Heart, Lung and Blood Institute, Bethesda, MD
1979-1981 Assistant Professor, Department of Pathology, Associate Staff
Member, Cardiovascular Research Institute, University of
California, San Francisco, CA
1981-1987 Associate Professor, Department of Pathology, University of
California, San Francisco, CA
1979-Present Senior Scientist, Gladstone Institute of Cardiovascular Disease,
San Francisco, CA
1981-Present Senior Staff Member, Cardiovascular Research Institute, University
of California, San Francisco, CA
1982-Present Associate Director, Gladstone Institute of Cardiovascular Disease,
San Francisco, CA
1987-Present Professor, Department of Pathology, University of
California, San Francisco, CA
PROFESSIONAL SOCIETIES AND HONORS
Metropolitan Life Foundation Award for Medical Research-1994; Merck Frosst
Canada Distinguished Lecturer-1993; Clinical Institute of Montreal Distinguished
Lecturer-1983; NIH Physiological Chemistry Study Section 1993-1995; Chairman,
American Heart Association (AHA) AHA Arteriosclerosis Council Nominating
Committee 1993-1995; Chair, AHA Arteriosclerosis Council Credentials Committee
1984-1986; Editorial Board Member of Arteriosclerosis, Thrombosis, and Vascular
Biology and the Journal of Lipid Research; AHA Arteriosclerosis Council Fellow;
National Research Council Postdoctoral Research Associate; American Association
for the Advancement of Science; American Chemical Society; New York Academy of
Sciences; American Society for Biochemistry and Molecular Biology; American
Crystallographic Association.
PUBLICATIONS (selected recent publications)
1. Weisgraber, K.H., Rall, S.C., and Mahley, R.W. (1981) Human E apoprotein
heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of
the apo-E isoforms. J. Biol. Chem. 256: 9077--9083.
2. Rall, S.C., Jr., Weisgraber, K.H., and Mahley, R.W. (1982) Human
apolipoprotein E: The complete amino acid sequence. J. Biol. Chem. 257:
4171--4178.
3. Weisgraber, K.H., Innerarity, T.L., Harder, K.J., Mahley, R.W., Milne,
R.W., Marcel, Y.L., and Sparrow, J.T. (1983) The receptor binding domain of
human apolipoprotein E: Monoclonal antibody inhibition of binding. J. Biol.
Chem. 258: 12348--12354.
4. Weisgraber, K.H., Rall, S.C., Jr., Mahley, R.W., Milne, R.W., Marcel, Y.L.,
and Sparrow, J.T. (1986) Human apolipoprotein E: Determination of the
heparin binding sites of apolipoprotein E3. J. Biol. Chem. 261: 2068--2076.

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5. Wetterau, J.R., Aggerbeck, L.P., Rall, S.C., Jr., and Weisgraber, K.H.
(1988) Human apolipoprotein E3 in aqueous solution. I. Evidence for two
structural domains. J. biol. Chem. 263: 6240--6248.
6. Aggerbeck, L.P., Wetterau, J.R., Weisgraber, K.H., Wu, C.-S.C., and
Lindgren, F.T. (1988) Human apolipoprotein in aqueous solution. II.
Properties of the amino-and carboxyl-terminal domains. J. Biol. Chem. 263:
6249--6258.
7. Weisgraber, K.H., Mahley, R.W., Kowal, R.C., Herz, J., Goldstein, J.L., and
Brown, M.S. (1990) Apolipoprotein C-I modulates interaction of
apolipoprotein E with (beta)-migrating very low density lipoproteins
((beta)-VLDL) and inhibits binding of (beta)-VLDL to low density
lipoprotein receptor-related protein. J. Biol. Chem. 265: 22453--22459.
8. Weisgraber, K.H. (1990) Apolipoprotein E distribution among human plasma
lipoproteins: Role of the cysteine-arginine interchange at residue 112. J.
Lipid Res. 31: 1503--1511.
9. Wilson, C., Wardell, M.R., Weisgraber, K.H., Mahley, R.W., and Agard, D.A.
(1991) Three-dimensional structure of the LDL receptor-binding domain of
human apolipoprotein E. Science 252: 1817--1822.
10. Westerlund, J.A., and Weisgraber, K.H. (1993) Discrete carboxyl-terminal
segments of apolipoprotein E mediate lipoprotein association and protein
oligomerization. J. Biol. Chem. 268: 15745--15750.
11. Weisgraber, K.H. (1994) Apolipoprotein E: structure-function relationships.
Adv. Protein Chem. 45: 249--302.
12. Strittmatter, W.J., Weisgraber, K.H., Huang, D., Dong, L.-M., Salvesen,
G.S., Pericak-Vance, M., Schmechel, D., Saunders, A.M., Goldgaber, D., and
Roses, A.D. (1993) Binding of (beta)A4 peptide to human apolipoprotein E:
Isoform-specific effects and implications for late-onset Alzheimer disease.
Proc. Natl. Acad. Sci. USA. 90: 8098--8102.
13. Weisgraber, K.H., Roses, A.D., and Strittmatter, W.J. (1994) The role of
apolipoprotein E in the nervous system. Curr. Opin. Lipidol. 5: 110--116.
14. Srittmatter, W.J., Weisgraber, K.H., Goedert, M., Saunder, A.M., Huang, D.,
Corder, E.H., Dong. L.-M., Jakes, R., Albers, M.J., Gilbert, J.R., Han,
S.-H., Hulette, C., Einstein, G., Schmechel, D.E., Pericak-Vance, M.A., and
Roses, A.D. (1994) Hypothesis: Microtubule instability and paired helical
filament formation in the Alzheimer disease brain as a function of
apolipoprotein E genotype. Exp. Neurol. 125: 163--171.
15. Nathan, B.P., Bellosta, S., Sanan, D.A., Weisgraber, K.H., Mahley, R.W.,
and Pitas, R.E. (1994) Differential effects of apolipoproteins E3 and E4 on
neuronal growth in vivo. Science 264: 850--852.
16. Dong, L.-M., Wilson, C., Wardell, M.R., Simmons, T., Mahley, R.W.,
Weisgraber, K.H., and Agard, D.A. (1994) Human apolipoprotein E: The role
of arginine-61 in mediating the lipoprotein preferences of the E3 and E4
isoforms. J. Biol. Chem. 269: 22358--22365.
17. Sanan, D.A., Weisgraber, K.H., Russel, S.J., Mahley, R.W., Huang, D.,
Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., Roses, A.D.,
and Strittmatter, W.J. (1994) Apolipoprotein E associates with (beta)
amyloid peptide of Alzheimer's disease to form novel monofibrils: Isoform
apoE4 associates more efficiently than aopE3. J. Clin. Invest. 94:
860--869.
18. Strittmatter, W.J., Saunders, A.M., Goedert, M., Weisgraber, K.H., Dong,
L.-M., Jakes, R., Huang, D., Pericak-Vance, M., Schmechel, D., and Roses,
A.D. (1994) Isoform-specific interactions of apolipoprotein E with
microtubule-associated protein tau: Implications for Alzheimer disease.
Proc. Natl. Acad. Sci. USA. 91: 11183--11186.
19. Wilson, C., T. Mau, Weisgraber, K.H., Wardell, M.R., Mahley, R.W., and
Agard, D.A. (1994) Salt bridge relay triggers defective LDL receptor
binding by a mutuant apolipoprotein. Structure 2: 713--718.
20. Weisgrabe, K.H., Pitas, R.E., and Mahley, R.W. (1994) Lipoproteins,
neurobiology, and Alzheimer's disease: Structure and function of a
apolipoprotein E. Curr. Opin. Struct. Biol. 4: 507-515.
21. Weisgraber, K.H., Newhouse, Y.M., and McPherson, A. (1994) Crystallization
and preliminary X-ray analysis of human plasma apolipoprotein C-I. J. Mol.
Biol. 236: 282--384.
22. Evans, K.C., Berger, E.P., Cho. C.-G., Weisgraber, K.H., and Lansbury,
P.T., Jr. (1995) Apolipoprotein E is a kinetic but not a thermodynamic
inhibitor of amyloid formation: Implications for the pathogenesis and
treatment of Alzheimer disease. Proc. Natl. Acad. Sci. USA 92: 763--767.

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BIOGRAPHICAL SKETCH

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NAME POSITION TITLE
Robert E. Pitas Senior Scientist

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EDUCATION/TRAINING (Begin with baccalaureate or other initial professional
education, such as nursing, and include postdoctoral training.)
- --------------------------------------------------------------------------------
DEGREE
INSTITUTION AND LOCATION (if applicable) YEAR(S) FIELD OF STUDY
- --------------------------------------------------------------------------------
University of Rhode Island, Kingston, RI B.S. 1965 Chemistry
University of Connecticut, Storrs, CT Ph.D. 1976 Nutrition/
Biochemistry

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RESEARCH AND PROFESSIONAL EXPERIENCE: Concluding with present position, list, in
chronological order, previous employment, experience, and honors. Include
present membership on any Federal Government public advisory committee. List, in
chronological order, the titles, all authors, and complete references to all
publications during the past three years and to representative earlier
publications pertinent to this application. If the list of publications in the
last three years exceeds two pages, select the most pertinent publications. DO
NOT EXCEED TWO PAGES.
EMPLOYMENT AND EXPERIENCE
1969-1970 Research Assistant I, Department of Animal Industries, University
of Connecticut, Storrs, CT
1973-1976 Research Assistant II, Department of Nutritional Sciences,
University of Connecticut, Storrs, CT
1976-1979 Principal Scientist, Meloy Laboratories, Inc., Springfield, VA
1979-1984 Assistant Professor, Department of Pathology, University of
California, San Francisco, CA
1979-Present Senior Scientist, Gladstone Institute of Cardiovascular Disease,
San Francisco, CA
1984-Present Associate Staff Member, Cardiovascular Research Institute,
University of California, San Francisco, CA
1984-1991 Associate Professor, Department of Pathology, University of
California, San Francisco, CA
1991-Present Professor, Department of Pathology, University of California,
San Francisco, CA
PROFESSIONAL SOCIETIES AND HONORS
Honored Student Award from American Oil Chemists' Society; American Heart
Association-Arteriosclerosis Council; American Institute of Nutrition; Member,
Society for Neuroscience; Sigma Xi; Index Editor for the journal Lipids,
1978-1986; Associate Editor for the journal Lipids, 1986-present.
PUBLICATIONS (selected recent publications)
1. Pitas, R.E., Innerarity, T.L., Arnold, K., and Mahley, R.W. (1979) Rate and
equilibrium constants for binding of apo-E HDLc (a cholesterol-inducted
lipoprotein) and low density lipoproteins to human fibroblasts: Evidence
for multiple receptor binding of apo-E HDLc. Proc. Natl. Acad. Sci. U.S.A.
76: 2311--2315.
2. Pitas, R.E., Innerarity, T.L., and Mahley, R.W. (1980) Cell surface
receptor binding of phospholipid protein complexes containing different
ratios of receptor-active and -inactive E apoprotein. J. Biol. Chem. 255:
5454--5460.
3. Pitas, R.E., Boyles, J., Mahley, R.W., and Bissell, D.M. (1985) Uptake of
chemically modified low density lipoproteins in vivo is mediated by
specific endothelial cells. J. Cell Biol. 100: 103--117.
4. Ignatius, M.M., Shooter, E.M., Pitas, R.E., and Mahley, R.W. (1987)
Lipoprotein uptake by neuronal growth cones in vitro. Science 236:
959--962.
5. Pitas, R.E., Boyles, J.K., Lee, S.H., Hui, D., and Weisgraber, K.H. (1987)
Lipoproteins and their receptors in the central nervous system:
Characterization of the lipoproteins in cerebrospinal fluid an
identification of apolipoprotein B,E (low density lipoprotein) receptors in
brian. J. Biol. Chem. 262: 14352--14360.
6. Pitas, R.E., Boyles, J.K. Lee, S.H., Hui, D., and Mahley, R.W. (1987)
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein
E-containing lipoproteins. Biochim. Biophys. Acta 917: 148-161.
7. Boyles, J.K. Zoellner, C.D., Anderson, L.J., Kosik, L.M., Pitas, R.E.,
Weisgraber, K.H., Hui, D.Y., Mahley, R.W., Gebicke-Haerter, P.J., Ignatius,
M.J., and Shooter, E.M. (1989) A role for apolipoprotein E, apolipoprotein
A-I, and low density lipoprotein receptors in cholesterol transport during
regeneration and remyelination of the rat sciatic nerve. J. Clin. Invest.
83: 1015--1031.

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8. Simonet, W.S., Bucay, N., Lauer, S.J., Wirak, D.O., Stevens, M.E.,
Weisgraber, K.H., Pitas, R.E., and Taylor, J.M. (1990) In the absence of a
downstream element, the apolipoprotein E gene is expressed at high levels
in kidneys of transgenic mice. J. Biol. Chem. 265: 10809--10812.
9. Pitas, R.E. (1990) Expression of the acetyl low density lipoprotein
receptor by rabbit fibroblasts and smooth muscle-cells: Up-regulation by
phorbol esters. J Biol. Chem. 265: 12722--12727.
10. Simonet, W.S., Bucay, N., Pitas, R.E., Lauer, S.J., and Taylor, J.M. (l99l)
Multiple tissue-specific elements control the apolipoprotein E/C-I gene
locus in transgenic mice. J. Biol. Chem. 266: 8651--8654.
11. Arnold, K.S., Innerarity, T.L., Pitas, R.E., and Mahley, R.W. (1992)
Lipoprotein-receptor interactions. In: Lipoprotein Analysis. A Practical
Approach. Converse, C.A. and Skinner, E.R. eds. Oxford University Press,
Oxford, England. pp. 145-168.
12. Pitas, R.E., and Mahley, R.W. (1992) Analysis of tissue lipoproteins. In:
Lipoprotein Analysis. A Practical Approach. Converse, C.A. and Skinner,
E.R., eds. Oxford University Press, Oxford, England. pp. 215--242.
13. Handelmann, G.E., Boyles, J.K., Weisgraber, K.H., Mahley, R.W., and Pitas,
R.E. (1992) Effects of apolipoprotein E, B-very low density lipoproteins,
and cholesterol on the extension of neurites by rabbit dorsal root ganglion
neurons in vitro. J. Lipid Res. 33: 1677--1688.
14. Pitas, R.E., Friera, A., McGuire, J., and Dejager, S. (1992) Further
characterization of the acetyl LDL (scavenger) receptor expressed by rabbit
smooth muscle cells and fibroblasts. Arterioscler. Thromb. 12: 1235--1244.
15. Lee, K.-D., Pitas, R.E., and Papahadjopoulos, D. (1992) Evidence that the
scavenger receptor is not involved in the uptake of negatively charged
liposomes by cells. Biochim. Biophys. Acta 1111: 1--6.
16. Dejager, S., Mietus-Snyder, M., and Pitas, R.E. (1993) Oxidized low density
lipoproteins bind to the scavenger receptor expressed by rabbit smooth
muscle cells and macrophages. Arterioscler. Thromb. 13: 371--378.
17. Dejager, S., Mietus-Snyder, M., Friera, A., and Pitas, R.E. (1993) Dominant
negative mutations of the scavenger receptor: Native receptor inactivation
by expression of truncated variants. J. Clin. Invest. 92: 894--902.
18. Mas-Oliva, J., Arnold, K.S., Wagner, W.D., Phillips, D.R., Pitas, R.E., and
Innerarity, T.L. (1994) Isolation and characterization of a
platelet-derived macrophage-binding proteoglycan. J. Biol. Chem. 269:
10177--10183.
19. Nathan, B.P., Bellosta, S., Sanan, D.A., Weisgraber, K.H., Mahley, R.W.,
and Pitas, R.E. (1994) Differential effects of apolipoproteins E3 and E4 on
neuronal growth in vitro. Science 264: 850--852.
20. Weisgraber, K.H., Pitas, R.E., and Mahley, R.W. (1994) Lipoproteins,
neurobiology, and Alzheimer's disease: Structure and function of
apolipoprotein E. Curr. Opin. Struct. Biol. 4: 507--515.
21. Mahley, R.W., Nathan, B.P., Bellosta, S., and Pitas, R.E. (1995)
Apolipoprotein E: Impact of cytoskeletal stability in neurons and the
relationship to Alzheimer's disease. Curr. Opin. Lipidol. 6: 86--91.
22. Nathan, B.P., Chang, K-C., Bellosta, S., Brisch, E., Ge, N., Mahley, R.W.,
and Pitas, R.E. (1995) The inhibitory effect of apolipoprotein E4 on
neurite outgrowth is associated with microtubule depolymerization. J. Biol.
Chem. 270: 19791--19799.
23. Gong, Q. and Pitas, R.E. (1995) Synergistic effects of growth factors on
the regulation of smooth muscle cell scavenger receptor activity. J. Biol.
Chem. 270: 21670--21678.
24. Holtzman, D.M., Pitas, R.E., Kilbridge, J., Nathan, B., Mahley, R.W., Bu,
G., and Schwartz, A.L. (1995) LRP mediates apolipoprotein E-dependent
neurite outgrowth in a CNS-derived neuronal cell line. Proc. Natl. Acad.
Sci. USA. 92: 9480--9484.
25. Bellosta, S., Nathan, B.P., Orth, M., Dong, L.-M., Mahley, R.W., and Pitas,
R.E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in
mouse neuroblastoma cells produces differential effects on neurite
outgrowth. J. Biol. Chem. 270: 27063--27071.
26. Weisgraber, K.H., Pitas, R.E., and Mahley, R.W. (1995) Role of
apolipoprotein E in Alzheimer's disease. In: Atherosclerosis X. Woodford,
F.P., Davignon, J., and Sniderman, A., eds. Elsevier Science Publishers,
Amsterdam. pp. 670-674.
27. Young, S.G., Cham, C.M., Pitas, R.E., Burri, B.J., Connolly, A., Flynn, L.,
Pappu, A.S., Wong, J.S., Hamilton, R.L., and Farese, R.V., Jr. (1995) A
genetic model for absent chylomicron formation: Mice producing
apolipoprotein B in the liver, but not in the intestine. J. Clin. Invest.
96: 2932--2946.
28. Mahley, R.W., Nathan, B.P., and Pitas, R.E. Apolipoprotein E: Structure,
function, and possible roles in Alzheimer's disease. Ann. N.Y. Acad. Sci.
In press.

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BIOGRAPHICAL SKETCH

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NAME POSITION TITLE
Lennart Mucke Scientist II/Associate Professor

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EDUCATION/TRAINING (Begin with baccalaureate or other initial professional
education, such as nursing, and include postdoctoral training.)
- --------------------------------------------------------------------------------
DEGREE
INSTITUTION AND LOCATION (if applicable) YEAR(S) FIELD OF STUDY
- --------------------------------------------------------------------------------
Freie Universitat Berlin, Germany 1976-1980 Medicine
Max-Planck-Institute for Biophysical
Chemistry, Gottingen, Germany 1979-1982 Neurobiology
Georg-August-Universitat, M.D. 1980-1982 Medicine
Gottingen, Germany
- --------------------------------------------------------------------------------

RESEARCH AND PROFESSIONAL EXPERIENCE: Concluding with present position, list, in
chronological order, previous employment, experience, and honors. Include
present membership on any Federal Government public advisory committee. List, in
chronological order, the titles, all authors, and complete references to all
publications during the past three years and to representative earlier
publications pertinent to this application. If the list of publications in the
last three years exceeds two pages, select the most pertinent publications.
DO NOT EXCEED TWO PAGES.
EMPLOYMENT AND EXPERIENCE
1982-1984 Research Fellow, Department of Neurobiology, Max-Planck-Institute
for Biophysical Chemistry, Gottingen, Germany
1984-1985 Resident, Department of Internal Medicine, The Cleveland Clinic,
Cleveland, OH
1985-1988 Resident, Department to Neurology, Massachusetts General Hospital
and Harvard Medical School, Boston, MA
1988 Chief Resident, Department of Neurology, Massachusetts General
Hospital and Harvard Medical School, Boston, MA
1988-1990 Postdoctoral Fellow, Viral Immunobiology Laboratory, The Scripps
Research Institute, La Jolla, CA
1990-1994 Assistant Professor, Department of Neuropharmacology, The Scripps
Research Institute, La Jolla, CA
1994-1995 Associate Professor, Department of Neuropharmacology, The
Scripps Research Institute, La Jolla, CA
1996-Present Scientist II, Gladstone Molecular Neurobiology Program, The
Gladstone Institute of Cardiovascular
Disease, San Francisco, CA
1996-Present Associate Professor, Department of Neurology and Program in
Biological Sciences (Neuroscience Program), University of
California, San Francisco, CA
PROFESSIONAL SOCIETIES AND HONORS
Society for Neuroscience; American Society for Virology; Editorial Board,
Transgenics; Thyssen Foundation Career Development Award; National Multiple
Sclerosis Society Fellowship Award; Weil Award for the Best Paper on
Experimental Neuropathology; Alzheimer's Disease Association Faculty Scholar
Award; National Multiple Sclerosis Society Faculty Scholar Award (Harry Weaver
Neuroscience Scholarship).
BOARD CERTIFICATION
American Board of Psychiatry and Neurology
PUBLICATIONS (selected recent publications)
1. Abraham, C.R., Razzaboni, B.L., Papastoitsis, G., Picard, E., Kanemaru, K.,
Meckelein, B., and Mucke, L. (1992) Purification and cloning of brain
proteases capable of degrading the (beta)-amyloid precursor protein. Ann.
N.Y. Acad. Sci. 674: 174--179.
2. Campbell, I.L., Abraham, C.R., Masliah, E., Kemper, P., Inglis, J.D.,
Oldstone, M.B.A., and Mucke, L. (1993) Neurologic disease induced in
transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl.
Acad. Sci. USA 90: 10061--10065.

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3. Mucke, L., and Eddleston, M. (1993) Astrocytes in infectious and
immune-mediated diseases of the central nervous system. FASEB J. 7:
1226--1232.
4. Mucke, L. and Rockenstein, E.M. (1993) Prolonged delivery of transgene
products to specific brain regions by migratory astrocyte grafts.
Transgenics 1: 3--9.
5. Eddleston, M.P. and Mucke, L. (1993) Molecular-profile of reactive
astrocytes. Implications for their role in neurologic disease. Neuroscience
54: 15--36.
6. Abraham,C.R., Kanemaru, K., and Mucke, L. (1993) Expression of cathepsin
G-like and [alpha]-1 antichymotrypsin-like proteins in reactive astrocytes.
Brain Res. 621: 222--232.
7. Rall, G.F., Mucke, L., Nerenberg, M., and Oldstone, M.B.A. (1994) A
transgenic mouse model to assess the interaction of cytotoxic T lymphocytes
with virally infected, class I MHC-expressing astrocytes. J. Neuroimmunol.
52: 61--68.
8. Toggas, S.M., Masliah, E., Rockenstein, E.M., Rall, G.F., Abraham, C.R.,
and Mucke, L. (1994) Central nervous system damage produced by expression
of the HIV-1 coat protein gpl20 in transgenic mice. Nature 367: 188--193.
9. Mucke, L., Masliah, E., Johnson, W.B., Ruppe, M.D., Alford, M.,
Rockenstein, E.M., Forss-Petter, S., Pietropaolo, M., Mallory, M., and
Abraham, C.R. (1994) Synaptotrophic effects of human amyloid (beta) protein
precursor in the cortex of transgenic mice. Brain Res. 666: 151--167.
10. Johnson, W.B., Ruppe, M.D., Rockenstein, E.M., Price, J., Sarthy, V.P.,
Verderber, L.C., and Mucke, L. (1995) Indicator expression directed by
regulatory sequences of the glial fibrillary acidic protein (GFAP) gene: In
vivo comparison of distinct GFAP-lacZ transgenes. Glia 13: 174--184.
11. Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P.,
Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido,
T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Leibowitz, P.,
Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala,
M., Mucke, L., Paganini, L., and Penniman, L. (1995) Alzheimer-type
neuropathology in transgenic mice overexpressing V717F (beta)-amyloid
precursor protein. Nature 373: 523--527.
12. Wyss-Coray, T., Feng, L., Masliah, E., Ruppe, M.D., Lee, H.S., Toggas,
S.M., Rockenstein, E.M., and Mucke, L. (1995) Increased central nervous
system production of extracellular matrix components and development of
hydrocephalus in transgenic mice overexpressing transforming growth
factor-(beta)1. Am. J. Pathol. 147: 53--67.
13. Mucke, L., Abraham, C.R., Ruppe, M.D., Rockenstein, E.M., Toggas, S.M.,
Alford, M., and Masliah, E. (1995) Protection against HIV- 1 gp120-induced
brain damage by neuronal overexpression of amyloid protein precursor (APP).
J. Exp. Med. 181: 1551--1556.
14. Rockenstein, E., McConlogue, L., Tan, H., Gordon, M., Power, M., Masliah,
E., and Mucke, L. (1995) Levels and alternative splicing of amyloid (beta)
protein-precursor (APP) transcripts in brains of transgenic mice and humans
with Alzheimer's disease. J. Biol. Chem. 270: 28257--28267.
15. Verderber, L., Johnson, W., Mucke, L., and Sarthy, V. (1995) Differential
regulation of a GFAP-lacZ transgene in retinal astrocytes and Muller cells.
-- Invest. Ophthalmol. Vis. Sci. 36: 1137--1143.
16. Mucke, L., Masliah, E., and Campbell, I.L. (1995) Transgenic models to
assess the neuropathogenic potential of HIV-1 proteins and cytokines. Curr.
-- Top. Microbiol. Immunol. 202: 187--205.
17. Rall, G.F., Mucke, L., and Oldstone, M.B.A. (1995) Consequences of
cytotoxic T lymphocyte interaction with MHC class I-expressing neurons in
-- vivo. J. Exp. Med. 182: 1201--1212.
18. Borrow, P., Cornell, J.L., Ruppe, M.D., and Mucke, L. (1995)
Immunization-induced inflammatory infiltration of the CNS in transgenic
mice expressing a foreign antigen in astrocytes. J. Neuroimmunol. 61:
133--149.
19. Toggas, S.M., Masliah, E., and Mucke, L. (1995) Memantine blocks HIV-1
gpl20-induced neuronal damage in the central nervous system of transgenic
-- mice. Brain Res. 706: 303--307.
20. Masliah, E., Mallory, M., Alford, M., Ge, N., and Mucke, L. (1995) Abnormal
synaptic regeneration in hAPP695 transgenic and apoE knockout mice. In
Research Advances in Alzheimer's Disease and Related Disorders. Iqbal, K.,
Mortimer, J., Winblad, B., and Wisniewski, H. (eds), John Wiley & Sons, pp.
405--414.
21. Mucke, L., Abraham, C.R., and Masliah, E. (1996) Neurotrophic and
neuroprotective effects of hAPP in transgenic mice. Ann. N. Y. Acad. Sci.
777: -- 82--89.
22. Wysss-Coray, T., Masliah, E., Toggas, S.M., Lee, H.S., and Mucke, L. (1996)
Dysregulation of signal transduction pathways as a potential mechanism of
nervous system alterations in HIV-1 gpl20 transgenic mice and humans with
HIV-1 encephalitis. J. Clin. Invest. 97: 789--798.

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