# ANALYSIS OF THE APP GENE IN ALZHEIMER'S DISEASE

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 1993 · $222,627

## Abstract

Accumulation of amyloid in plaques is a characteristic feature of
Alzheimer's disease (AD) and may be an important factor in the pathogenesis
this disorder.  These amyloid deposits contain beta-amyloid encoded by
exons 16 and 17 of the amyloid precursor protein (APP) gene.  For some AD
patients, disturbance in the structure or function of the APP gene may
contribute to amyloid accumulation.  This primary role for the APP gene is
supported by the recent finding that 3 mutations altered the same APP codon
in 7 unrelated familial AD kindreds.  These-mutations are rare and it is
quite likely that there are other AD-specific APP mutations.  I will use
denaturing gradient gel electrophoresis and direct DNA sequencing to detect
additional APP mutations samples from at least 300 AD patients.  I have
used these extremely sensitive methods to detect a novel mutation in the
prion gene in Creutzfeldt-Jakob disease.  Defining the precise nature and
location of APP mutations will tremendously advance our understanding of
the mechanisms by which APP contributes to amyloid formation in AD.

For some Alzhiemer's patients, amyloid accumulation could be related not to
a structural change in the APP gene but to disturbance in this gene's
transcriptional regulation or splicing pattern.  There is evidence, for
example, that the pattern of APP mRNA splicing is altered in brain regions
which accumulate amyloid.  I have recently discovered marked,
tissue-specific differences in the abundance of APP mRNA transcripts
arising from normal and mutant APP alleles in samples from AD patients.
This may be an unusual finding because both alleles of most autosomal genes
are presumed to be similarly regulated in a given tissue.  These findings
suggest that the APP gene may be under complex and relatively unique
regulation.  I will extend these investigations by determining whether
marked differences in the abundance of mRNA derived from normal and mutant
APP alleles are due to tissue-specific differences in the rates of
transcription or variable mRNA stability.  Greater understanding of the
tissue-specific regulation of APP mRNA transcription, splicing,
termination, and stability is extremely important because it is likely
that, for some AD patients, disturbance of this regulation contributes to
amyloid formation.

## Key facts

- **NIH application ID:** 3122656
- **Project number:** 5R01AG010691-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **SAM.gov UEI:** GNJ7BBP73WE9
- **Principal Investigator:** JOHN K. FINK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $222,627
- **Award type:** 5
- **Project period:** 1992-09-15 → 1995-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122656

## Citation

> US National Institutes of Health, RePORTER application 3122656, ANALYSIS OF THE APP GENE IN ALZHEIMER'S DISEASE (5R01AG010691-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122656. Licensed CC0.

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