# TRANSGENIC MOUSE MODELS FOR ALZHEIMER'S DISEASE

> **NIH NIH R01** · MC LAUGHLIN RESEARCH INSTITUTE · 1993 · $164,003

## Abstract

The role of the Beta/A4-amyloid precursor protein gene (APP) on Chr 21 in
Alzheimer's disease(AD) is not clear.  Two lines of evidence suggest a
pivotal role for APP in AD.  First, individuals with Down's syndrome
(trisomy 21) exhibit accelerated development of the neuropathological
features of AD, including abundant amyloid plaques.  Overexpression of APP
may be responsible for AD-like changes in trisomy 21, though there is no
direct evidence that this is the case.  Second, linkage between a missense
mutation at APP residue 717 and early onset familial AD (FAD) recently has
been demonstrated.  Unfortunately, no mouse model exists that recapitulates
the features of AD.  Results from transgenic (Tg) muse experiments on the
neurodegenerative diseases caused by prions suggest that the key to
mimicking the pathological changes of AD in short lived rodents is
obtaining dramatic overexpression of the proteins involved.  One line of Tg
mice with modest overexpression of APP695 encoded in a minigene construct
is currently available.  By use of a cosmid transgenic expression vector
(cosTet), developed to express hybrid prion protein genes, additional Tg
line overexpressing the 695, 751, and 770 isoforms of APP will be produced.
By creating APP 'cassettes' for insertion into cosTet, FAD-linked mutations
and the mutation linked with hereditary cerebral hemorrhage with
amyloidosis-Dutch can be introduced into the expression vector.  This will
allow testing the hypothesis that these mutations cause disease.  Because
it is possible that APP overexpression is not a proximal cause of AD,
experiments are included that have the potential to induce AD-like changes
in Tg mice.  Mouse neurological mutations that cause neurodegeneration will
be combined with APP transgenes to test the hypothesis that progressive
death of cells overexpressing APP initiates Beta-amyloid accumulation and
plaque formation.  Similar experiments using neurotropic retrovirus or
scrapie prions as the neurodegenerative agents are also proposed.  Tg mice
overexpressing APP, either normal or mutant, also will provide a powerful
tool for examining the influence of other genes that may be involved in Ad,
and will allow direct testing of the role of the ratio of expression of the
different isoforms of APP in Ad.  The value of a mouse model for AD
warrants this novel approach.

## Key facts

- **NIH application ID:** 3122628
- **Project number:** 5R01AG010681-03
- **Recipient organization:** MC LAUGHLIN RESEARCH INSTITUTE
- **SAM.gov UEI:** HFVPWLV7WAJ3
- **Principal Investigator:** George A. Carlson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $164,003
- **Award type:** 5
- **Project period:** 1991-09-29 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122628

## Citation

> US National Institutes of Health, RePORTER application 3122628, TRANSGENIC MOUSE MODELS FOR ALZHEIMER'S DISEASE (5R01AG010681-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122628. Licensed CC0.

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