# Project 3: Roles of Tau Levels, Sequence and Interactors in Neural Network Dysfunction of Alzheimer's Disease

> **NIH NIH P01** · J. DAVID GLADSTONE INSTITUTES · 2022 · $867,557

## Abstract

PROJECT 3 – 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,
we will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels
of human tau that is (1) wildtype, as in most AD patients, (2) carries the A152T substitution, which increases AD
risk, or (3) bears the P301S mutation, which causes FTLD and is widely used in overexpression models.
Comprehensive functional, pathological, and transcriptomic analyses of the new models, 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. We hypothesize that tau species that increase AD risk or cause FTLD
differ in their effects on the integrity and function of neurons and neural networks, especially when combined
with Aβ and apoE4. 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 conventional models. We will therefore use tau-targeting antisense oligonucleotides (ASOs)
to (1) determine whether reducing human tau can diminish neural network dysfunction, neurodegeneration and
cognitive decline in models co-expressing human Ab and apoE4, (2) define the optimal timing for this
intervention, and (3) reveal the most critical co-pathogenic mechanisms of tau. We hypothesize that ASO-
mediated tau reduction will diminish not only tau pathology in one or more of the new models, but also synaptic
deficits, neural network dysfunction, and cognitive deficits, even though it is unlikely to reduce amyloid deposition
or plaque-associated microgliosis. This experiment should help determine when tau reduction must be initiated
relative to the onset of cognitive deficits for it to have therapeutic benefits in AD-relevant contexts. Single-
nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes
and novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of
tau reduction...

## Key facts

- **NIH application ID:** 10461845
- **Project number:** 5P01AG073082-02
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Lennart Mucke
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $867,557
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461845

## Citation

> US National Institutes of Health, RePORTER application 10461845, Project 3: Roles of Tau Levels, Sequence and Interactors in Neural Network Dysfunction of Alzheimer's Disease (5P01AG073082-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10461845. Licensed CC0.

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