# ALZHEIMERS DISEASE STUDIES USING HSV GENE TRANSFER

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 1991 · $176,503

## Abstract

The overall aim of this research is to use aneurovirulent mutant forms of
Herpes simplex virus (HSV) as direct gene transfer vectors to study the
pathogenesis of Alzheimer's disease (AD).  We will test the hypothesis
that altered production or aberrant processing of amyloid precursor
protein (APP) is directly responsible for the development of
Alzheimer-like pathology in vivo.  Genetically engineered recombinant HSV
vectors will be used to introduce specific forms of the APP gene into the
mature rat brain in a manner in which these genes are exclusively
expressed from an otherwise quiescent viral genome during latency.  We
will also test a related hypothesis that chronic production of nerve
growth factor (NGF) can rescue basal forebrain cholinergic neurons from
age-related cell death using a similar vector.  Finally, we will
determine whether there exists an interrelationship between APP and NGF
gene expression in brain using a combination of virus vectors.  Three
specific aims are outlined: (i) We will first complete development of HSV
as a gene transfer latency vector for the rat CNS.  The virus will be
engineered to establish life-long latent infections in specific brain
regions following direct stereotactic injection.  Lac-z gene cassettes
will be introduced into the virus vector at the U(s)3 locus using a Pl
phage cre-lox recombination system and B-galactosidase expression from
the latent HSV genomes will be induced in hippocampal cell populations
using either the latency-specific (LAT) promoter or the neuron-specific
neurofilament (NF) promoter.  We will confirm that there is no virus
-induced neuropathology created by the recombinant vector alone. (ii) The
genes encoding for the full length APP, with and without the protease
inhibitor insert, and the gene for the A4 fragment of APP, will be
similarly recombined into the HSV latency vector and introduced into the
hippocampus.  We will determine whether any of these recombinants cause
Alzheimer-like pathology in the rat brain, and whether these gene
products effect the level of NGF expression. (iii) The gene for NGF will
be expressed in hippocampus using an HSV::NGF recombinant latency vector
in order to determine whether chronic NGF production can reverse the
age-related loss of basal forebrain cholinergic neurons.  We will also
use expression from this vector in brain to determine whether chronic
overproduction of NGF effects endogenous brain expression, and whether
NGF delivered in this manner plays any role in modulating specific CNS
pathology.___

## Key facts

- **NIH application ID:** 3121331
- **Project number:** 1R01AG009470-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **SAM.gov UEI:** MKAGLD59JRL1
- **Principal Investigator:** Joseph C Glorioso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $176,503
- **Award type:** 1
- **Project period:** 1991-02-01 → 1995-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3121331

## Citation

> US National Institutes of Health, RePORTER application 3121331, ALZHEIMERS DISEASE STUDIES USING HSV GENE TRANSFER (1R01AG009470-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3121331. Licensed CC0.

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