# AMYLOIDOGENESIS ROLE OF REACTIVE ASTROCYTES

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 1992 · $225,308

## Abstract

In normal aging of humans and, to a much greater extent, in Alzheimer;s
disease (AD) and Down's Syndrome, extracellular deposits of amyloid
accumulate in senile plaques and blood vessel walls.  Since the amyloid is
among the first markers of aging in humans, we hypothesize here that the
abnormal deposition of amyloid is detrimental to its surroundings, causes
the neuritic response, and possibly, the tangle formation, synaptic and
neuronal cell loss and finally cognitive deficits.  One of the amyloid
components is the beta-protein, a 4Kd fragment of a much larger protein
precursor.  We believe that an abnormal proteolytic degradation of the
beta-protein precursor (betaPP) must occur in order to generate very
hydrophobic fragments which can aggregate and precipitate as amyloid.  A
hint for an abnormal processing of the beta-PP comes from the second
component found very tightly associated with the beta-protein, the serine
protease inhibitor, alpha-1-antichymotrypsin (ACT).  Finding ACT in the
amyloid led us search for proteases which may be involved in the
proteolytic degradation of the betaPP, we identified a protease fraction
able to cleave at the peptides made according to known sequences of the
betaPP, we identified a protease fraction able to cleave at the N-terminus
of the beta-protein and are looking for a second protease that normally
cleaves in the middle of the beta-protein.  Here, we propose to study the
appearance of amyloid in the aging and Ad brain and to correlate its
formation with the presence of our proteases.  In order to accomplish this
goal, we need to purify the proteases to homogeneity, to sequence them and
to produce monoclonal and polyclonal antibodies to them.  The antibodies
will provide tools for determining the distribution of the enzymes in brain
and to clone their genes by screening expression cDNA libraries.  The
cloned cDNAs can be then sequenced and also used as probes on RNA blots to
establish whether the proteases expression changes with increasing age or
in various parts of the brain, especially those involved in amyloid
deposits.  The cloned cDNAs will then be used to identify the cells
producing the enzymes by in situ hybridization and to localize the genes on
the human chromosome.  If the genes reside on chromosomes 21 or 19, the two
possible locations for a familial Alzheimer's disease gene (FAD), we will
perform linkage analysis using the proteases cDNAs to determine if either
one of the genes coding for our proteases is the FAD gene.  The reactive
astrocytes are a good candidate for amyloidogenesis, either by providing
their own betaPP or by means of secreting proteases and inhibitors involved
in betaPP degradation.  Here we will investigate the role of astrocytes in
amyloid formation by using primary rat astrocytes transfected with human
genes such as betaPP, ACT and the proteases, or by using human astrocytoma
or glioblastoma cell lines.  If we obtain an experimental system that can
produce amyloid in cel...

## Key facts

- **NIH application ID:** 3121849
- **Project number:** 5R01AG009905-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **SAM.gov UEI:** FBYMGMHW4X95
- **Principal Investigator:** CARMELA R ABRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $225,308
- **Award type:** 5
- **Project period:** 1991-05-01 → 1994-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3121849

## Citation

> US National Institutes of Health, RePORTER application 3121849, AMYLOIDOGENESIS ROLE OF REACTIVE ASTROCYTES (5R01AG009905-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3121849. Licensed CC0.

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