# PLAQUE AND TANGLE PATHOGENESIS IN ALZHEIMIERS DISEASE

> **NIH NIH R01** · UNIVERSITY OF OXFORD · 1993 · $78,330

## Abstract

The experiments outlined in this revised proposal reflect the PI's
longstanding interest in the role of amyloidotic and neurofibrillary
lesions in the pathogenesis of Alzheimer's disease (AD). They focus on
early events which may precede the formation of these pathological
abnormalities. Because there is yet no evidence that the beta-amyloid
protein precursor (betaAPP or pre-A4) gene is normal in AD, these
studies concentrate on possible transcriptional or posttranslational
events which could explain the excess progressive deposition of Beta-
amyloid protein (betaAP or A4) in the brain of patients with AD, as
compared to aged normals. It is unlikely that a single abnormality at
the protein level will account for amyloidosis varies widely among AD
brains, even among individuals with comparable numbers of plaques. Also,
many investigators now agree that there is a form of AD which lacks
neocortical tangles, and that this subset of patients cannot be
distinguished from AD cases with abundant tangles by clinical or
biochemical criteria. Hence, the proposed experiments address a series
of interrelated questions aimed at several aspects of altered brain
structure and function in AD. Specific Aim #1 analyzes what may be the
most prevalent lesion in AD brains - diffuse ("pre-amyloid") plaques.
These lesions have been identified as morphous BetaAP deposits
apparently lacking reactive neurites or glial cells. We hypothesize that
diffuse plaques may be a very early lesion and one that contains BetaAP
in a non-fibrillar (i.e., not amyloid) form. Specific Aim #2 explores an
entirely new area, the possibility that BetaAP is deposited outside the
brain in AD. The experiments aim to confirm and expand our strong
preliminary data showing specific BetaAP immunostanding in AD and aged
normal skin and colon, but not tissue from young (<60 yrs) controls.
Confirmation of this new data carries implications about the basic
mechanisms of BetaAP deposition. Specific Aim #3 proposes a detailed EM
study of amyloidotic vessels to look for the earliest
immunocytochemically detectable BetaAP deposits and asks if BetaAP is
present in vessels in a non-fibrillar form. In addition, the experiments
will determine if the vascular distribution of Beta-amyloid, which is
known to be segmental and focal, can be correlated with that of smooth
muscle cells and/or pericytes. If so, these cells may be important in
the processing/deposition of BetaAP in vessels. Specific Aim #4
addresses several issues concerning the normal function of BetaAPP,
using human cell lines stably transfected with full length BetaAPP
CDNAS. The emerging theme of growth-promoting properties of BetaAPP will
be examined. Taken together, the proposed experiments address features
of AD which may represent important pathogenetic steps in the evolution
of this common disease. This application represents a critical step in
the dedication of the PI's career to research on human neurodegenerative
disease.

## Key facts

- **NIH application ID:** 3120226
- **Project number:** 5R01AG008537-03
- **Recipient organization:** UNIVERSITY OF OXFORD
- **SAM.gov UEI:** G124UKMYGZJ6
- **Principal Investigator:** CATHERINE L JOACHIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $78,330
- **Award type:** 5
- **Project period:** 1992-01-17 → 1995-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3120226

## Citation

> US National Institutes of Health, RePORTER application 3120226, PLAQUE AND TANGLE PATHOGENESIS IN ALZHEIMIERS DISEASE (5R01AG008537-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3120226. Licensed CC0.

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