# NEUROTROPHIC FACTOR THERAPY FOR ALZHEIMER'S DISEASE

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 1993 · $173,838

## Abstract

Neuron cell death features prominently in the development of the nervous
system and is a key pathological component in neurodegenerative disorders
such as Alzheimer's disease (AD).  Currently, there is no effective
treatment for AD.  One view of pathogenesis suggests that neuronal death
in development and disease are due to activation of cell death genes and
that controlling expression of these genes will make it possible to
prevent degeneration.  Target-derived neurotrophic factors prevent
neuronal death in development; they also act to prevent degeneration
induced by lesions of mature neurons.  They may prevent cell death in AD.

It is our hypothesis that nerve growth factor (NGF) will prevent
selective, spontaneous degeneration of basal forebrain cholinergic neurons
(BFCN) in a recently developed animal model of AD.  The model is based on
the finding that all Down syndrome (DS) patients develop AD pathology,
including degeneration of BFCN.  Mouse trisomy (TS) 16 is an animal model
of DS. We have found that TS16 basal forebrain transplants demonstrate
atrophy of BFCN after several months in vivo.  NGF, or a vehicle control,
will be infused into the cerebral ventricle of adult female mice carrying
transplanted basal forebrain neurons from TS 16 and control (diploid)
fetuses.  The number and size of TS16 cholinergic neurons will be compared
to controls, and the incidence of extracellular amyloid and
neurofibrillary tangles will be assessed.  These studies will determine
whether or not NGF treatment prevents atrophy and death of BFCN and will
give evidence for or against NGF mediated toxicity.  If NGF is shown to be
both effective and safe, these studies would give strong support to NGF
trials in AD patients.  The NGF gene family members brain-derived
neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may also act on BFCN;
they will be tested for activity on lesioned BFCN and, when appropriate,
in the transplant model.

To pursue the goal of neurotrophic drug design, we will attempt to define
NGF domains important for receptor binding and activation.  The strategy
to be used is based on the fact that NGF, BDNF and N.T-3 activate distinct
populations of neurons.  Structural differences between them must lead to
activation of distinct receptors.  Chimeras in which variant domains from
BDNF or NT-3 replace those of NGF will be tested for activity and binding.
When activity is changed to that for the factor whose domains were
introduced, we will have identified structural regions important for NGF
receptor activation.

The proposed studies will markedly advance studies of neurotrophic therapy
by extending observations to an animal model of the BFCN degeneration.
NGF and neurotrophic factors related to NGF may be shown effective and
safe in preventing cholinergic cell death.  Finally, our studies will pave
the way for future neurotrophic design.

## Key facts

- **NIH application ID:** 3122604
- **Project number:** 5R01AG010672-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **SAM.gov UEI:** KMH5K9V7S518
- **Principal Investigator:** William C Mobley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $173,838
- **Award type:** 5
- **Project period:** 1991-09-29 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3122604

## Citation

> US National Institutes of Health, RePORTER application 3122604, NEUROTROPHIC FACTOR THERAPY FOR ALZHEIMER'S DISEASE (5R01AG010672-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3122604. Licensed CC0.

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