# TRANSGENIC MODELS TO STUDY ALZHEIMER'S DISEASE

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 1993 · $230,415

## Abstract

The dementia of Alzheimer's disease (AD) is accompanied by accumulation of
abnormal proteins in form of amyloid deposits in victims' brains.  We
hypothesize that these proteins are detrimental to surrounding brain cells
and are a major cause of the symptoms seen in AD.  To test this hypothesis
in the living organism, we propose to express human amyloid components,
specifically, different forms of mutated and non-mutated amyloid beta
protein precursors (APP695, 751, 770) and the protease inhibitor alpha1-
antichymotrypsin (ACT), in the brains of transgenic mice with the help of
recombinant DNA constructs.  CDNAS encoding these human proteins will be
recombined with transgenic vectors (derived from the neuroA-specific
enolase (NSE) gene and the glial fibrillary acidic protein (GFAP) gene) for
the neuron-specific (NSE) or astrocyte-specific (GFAP) expression of
foreign proteins in the brains of transgenic mice.  These vectors are
chosen because both neurons and astrocytes may function as a source of
amyloid proteins in AD.  The transgenes will be introduced into the
germline of mice by microinjection of fertilized egg cells.  Transgenic
mice will be analyzed for the expression of the human CDNAS at the RNA and
protein levels.  The transgenic mouse model will be characterized by
detailed neuropathologic and biochemical analysis.  A battery of
neurobehavioral tests will assess if overproduction of APP and/or ACT in
the brains of the transgenic mice induces impairment of memory/learning or
other forms of neurologic dysfunction.  Behavioral abnormalities will be
correlated with neuropathologic findings.  If amyloid components are
causative factors in the dementia of AD, inhibition of their formation,
deposition or action should allow treatment of the disease.  To help
predict their usefulness in the treatment of AD, protease inhibitors,
tachykinin agonists such as substance P, and other agents will be tested in
the transgenic models for their ability to inhibit the structural and
functional alterations induced by the overexpression of APP/ACT.  The
molecular mechanisms of drug actions and amyloid formation will be studied
in vivo as well as in explant cultures of transgenic nervous tissue.  This
project will assess in vivo the role the following factors could play in
the development of AD: i) different forms of APP, ii) an APP point mutation
found in familial AD, iii) neuronal vs. astroglial processing of APP, and
iv) protease inhibitors such as ACT.  The transgenic models proposed should
allow the efficient preclinical assessment of drugs aimed at different
manifestations of AD and facilitate the development of new therapeutic and
diagnostic strategies.

## Key facts

- **NIH application ID:** 3123333
- **Project number:** 5R01AG011385-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **SAM.gov UEI:** PHZJFZ32NKH4
- **Principal Investigator:** Lennart Mucke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $230,415
- **Award type:** 5
- **Project period:** 1992-09-01 → 1995-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123333

## Citation

> US National Institutes of Health, RePORTER application 3123333, TRANSGENIC MODELS TO STUDY ALZHEIMER'S DISEASE (5R01AG011385-02). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123333. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*