# Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease

> **NIH NIH P01** · J. DAVID GLADSTONE INSTITUTES · 2022 · $91,710

## Abstract

SUPPLEMENT – SUMMARY
Tau contributes to Alzheimer’s disease (AD) and many other brain diseases. However, it is uncertain how tau
causes neuronal dysfunction and degeneration, in part because experimental models are not optimized to
compare the relative pathogenicity of different tau species in disease-relevant contexts. Mutations in MAPT, the
gene encoding tau, cause frontotemporal lobar degeneration (FTLD) instead of AD. In contrast, the rare A152T
variant of tau increases risk for both types of diseases. These associations merit further exploration, especially
as models expressing FTLD-mutant tau are widely used to study tau in AD and to develop novel AD treatments.
Clinical AD onset is preceded by abnormal accumulations of amyloid-b (Ab) peptides in brain, and many AD
patients have at least one apolipoprotein (apo) E4 allele, the most important genetic risk factor for AD. Therefore,
Project 3 will generate new mouse models combining human Ab and apoE4 expression with near-physiological
levels of human tau that is wildtype, as in most AD patients, or carries the A152T substitution, which increases
AD risk. Comprehensive functional, pathological, and transcriptomic analyses of the new models, to be carried
out in collaboration with Projects 1, 2, and 4 and Core B, should yield new insights into differential effects of
these tau species and their roles in the pathogenesis of dementia. Project 3 will also investigate whether tau
species that increase AD risk or cause FTLD differ in their effects on the integrity and functions of neurons and
neural networks. Until we know which forms of tau are most pathogenic in different conditions, the most
pragmatic therapeutic approach to tau in our view is partial reduction of overall tau levels, which is well tolerated
and has benefits in more conventional models. We will therefore use tau-targeting antisense oligonucleotides to
reduce human tau levels in models co-expressing human Ab and apoE4. Single-nucleus/single-cell
transcriptomic analyses will be used to identify cell-type-specific gene expression changes as well as novel
molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau
reduction. These analyses will help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and
Ab that do or do not depend on tau. They could also identify novel molecular and cellular mechanisms that
mediate tau sequence-specific effects. The requested supplement will allow a postdoctoral scholar from a
background that is underrepresented in the health-related sciences to contribute to the experiments proposed in
Project 3 and, at the same time, to benefit from training within the larger context of this AD-focused
interdisciplinary program.

## Key facts

- **NIH application ID:** 10525204
- **Project number:** 3P01AG073082-01S1
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** YADONG HUANG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $91,710
- **Award type:** 3
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525204

## Citation

> US National Institutes of Health, RePORTER application 10525204, Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease (3P01AG073082-01S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10525204. Licensed CC0.

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