# SUBCELLULAR BASIS OF SYNAPTIC PATHOLOGY ALZHEIMER DIS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 1991 · $116,789

## Abstract

The cognitive alterations observed in Alzheimer's disease (AD) might be the
result of an extensive loss of cortico-cortico afferent combined with an
aberrant sprouting in the areas of synapse loss.  We hypothesize that in
those areas the dystrophic neurites scattered in the neuropil and in the
plaques originate in the abnormal axons and presynaptic terminals, as the
result of the aberrant sprouting where amyloid precursor protein (APP) and
growth associated protein (GAP-43) may play a role.

In order to understand the subcellular basic and mechanisms of response to
synapse loss and pathology in AD and its relationship to the neuritic
plaque formation, this project will utilize two approaches.  One is to
perform 3-D reconstructions of synapses, scattered dystrophic neurites and
neuritic plaques in AD cortex and the other is to develop an experimental
model of denervation with widespread dystrophic changes.  The 3-D
reconstructions will be performed from serial semithin sections obtained
from AD frontal cortex biopsies processed with a Silicon Graphics Iris
4D/210VGX workstation.  Reconstructions will also be performed from optical
sections obtained from the laser confocal imaging of double immunolabeled
sections of the AD frontal cortex.  The sections will be labeled with
fluorescent tagged antibodies that recognize presynaptic terminals and
dystrophic neurites with anti-synaptophysin and tau respectively.  We also
will analyze the role of APP and GAP-43 in the sprouting response in the AD
cortex by comparing the patterns of APP-immunoreactive synapses and
dystrophic neurites to those of GAP-43 and synaptophysin in double
immunolabeled sections.  The quantitative information derived from these
studies and 3-D images of the AD neuropil and neuritic plaques are expected
to provide important information about the relationship between the
pathological synapses in the neuropil and in the plaques with the
dystrophic neurites.

The other approach that we propose is to develop an animal model of
neocortical dystrophic changes.  For this study, rats will receive
unilateral aspirative lesion of the fronto-parietal cortex followed by the
injection of a neurotoxin that will alter the process of plasticity.  The
rationale is that AD pathogenesis may be a multi-step process in which
several sequential hits are necessary to damage the repair mechanisms in
the cortex.  In the first step, there is a widespread synapse loss in
cortex, followed by a neurotoxic event that eventually will lead to an
ineffective and abnormal repair process in the denervated regions.  The
main neurotoxin we will test is the phorbol 12-myristate 13-acetate (PMA).
The rationale behind using PMA in our model of denervation, is that it will
interfere with reinnervation, promote an aberrant sprouting response
similar to the one observed in AD, affect PKC and GAP-43, and promote the
expression of amyloid genes in rat.  We expect that this lesion and
neurotoxin combination will reproduce, in t...

## Key facts

- **NIH application ID:** 3122649
- **Project number:** 1R01AG010689-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **SAM.gov UEI:** UYTTZT6G9DT1
- **Principal Investigator:** ELIEZER MASLIAH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $116,789
- **Award type:** 1
- **Project period:** 1991-09-29 → 1997-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122649

## Citation

> US National Institutes of Health, RePORTER application 3122649, SUBCELLULAR BASIS OF SYNAPTIC PATHOLOGY ALZHEIMER DIS (1R01AG010689-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122649. Licensed CC0.

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