# ABNORMAL FIBROUS ASSEMBLIES OF ALZHEIMER'S DISEASE

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 1992 · $146,200

## Abstract

The hallmark morphological abnormalities of Alzheimer's disease (AD) are
deposits of amyloid fibers, which constitute neuritic plaques and
cerebrovascular amyloid, and paired helical filaments (PHF), which
constitute neurofibrillary tangles. The formation and accumulation of
these fibrous assemblies profoundly affect memory, language and
behavior. Our research is focused on the major protein of AD amyloid,
called beta/A4, and on the microtubule-associated protein tau, which is
a major cytoskeletal protein and an integral component of PHF. Using a
correlation of results from X-ray diffraction, electron microscopy and
Fourier-transform infrared spectroscopy, we plan to provide a detailed
description of the molecular and macromolecular structures of the
fibrous assemblies of AD. In addition, we will determine the forces that
promote their formation, the factors that underlie their stability, and
the specific residues that promote their folding. To accomplish our
objective, this proposal focuses on the following three Specific Aims:
(1) To test specific hypotheses regarding the self-assembly and
stability of synthetic beta/A4 homologues, and their interactions with
tissue components that are thought to promote their formation. The
hypotheses are: (i) electrostatic interactions involving the formation
of a salt-bridge within the core region of beta/A4 are crucial in
stabilizing the beta-pleated sheets of the fibrils; (ii) a single amino
acid residue change in the sequence of beta/A4 accounts for the
extremely high level of aggregation of amyloid fibrils in hereditary
cerebral hemorrhage with amyloidosis of the Dutch type; (iii) alpha-
anti-chymotrypsin (ACT) binds specifically to and alters the structure
of beta/A4, thus affecting its proteolytic processing; and (iv) sulfated
proteoglycans of brain extracellular matrix promote the polymerization
and/or aggregation of AD amyloid by electrostatic interactions involving
the sulfate groups. (2) To investigate the assembly of PHF from modified
forms of microtubule-associated tau protein. A microdialysis technique
originally developed for crystallizing membraneproteins will be used to
manipulate and control the gradual formation of PHF-like filaments.
Suitable samples will be subjected to X-ray diffraction, which is
expected to provide new details of PHF organization that has so far
resisted such analysis. (3) To develop molecular models of these
fibrillar assemblies based on constraints imposed by the biophysical and
ultrastructural results. We will continue to develop analytical tools
that will be used to interpret the fiber diffraction patterns and to
model details of fibril organization at the molecular level. In
achieving our objective, we hope to develop sufficient understanding for
the eventual rational development of diagnostic/therapeutic strategies
for AD, for related neurodegenerative diseases, and for amyloidoses in
general.

## Key facts

- **NIH application ID:** 3120289
- **Project number:** 2R01AG008572-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **SAM.gov UEI:** Z1L9F1MM1RY3
- **Principal Investigator:** DANIEL A KIRSCHNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $146,200
- **Award type:** 2
- **Project period:** 1989-08-02 → 1995-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3120289

## Citation

> US National Institutes of Health, RePORTER application 3120289, ABNORMAL FIBROUS ASSEMBLIES OF ALZHEIMER'S DISEASE (2R01AG008572-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3120289. Licensed CC0.

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