# Mechanisms of Susceptibility of Excitatory Neurons to Tau Pathology and Neurodegeneration in Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $777,842

## Abstract

Project summary
The hippocampus is important for learning and memory and is highly susceptible to aggregation of microtubule-
associated protein tau (MAPT) and neurodegeneration. Hippocampal and neocortical atrophy in Alzheimer’s disease
(AD) brains demonstrates degeneration predominantly in large glutamatergic pyramidal neurons in association cortices
while inhibitory interneurons and primary cortices are resistant to MAPT accumulation and degeneration. However, the
molecular mechanisms that cause damage and death of susceptible neurons are not understood. Developing a better
understanding of the molecular mechanisms causing vulnerability of excitatory neurons to damage and identifying
pathways that regulate tau-mediated neurodegeneration will be essential to unraveling the pathogenesis and
progression of AD and identifying potential therapeutic targets. The primary goal of this proposal is to identify pathways
that make excitatory neurons susceptible to tau accumulation and neurodegeneration, and identify potential therapeutic
targets for AD. One important limitation is the cellular heterogeneity of the mammalian brain. To overcome the cellular
heterogeneity, this proposal will innovatively use single cell RNA sequencing in fresh AD human brain tissue and viral
translating ribosome affinity purification (vTRAP) in a mouse model of tauopathy to generate transcriptional profiles of
excitatory and inhibitory neurons from vulnerable and resilient regions of the brain in the context of aging and
neurodegeneration. Global gene co-expression networks for excitatory and inhibitory neurons will be constructed
through Weighted Interaction Network Analysis (WINA) and Multiscale Embedded Gene co-Expression Network
Analysis (MEGENA). WINA and MEGENA derived modules will then be associated with AD and the top key drivers of
the modules most associated with AD will become the candidate targets for experimental validation. We will also identify
distinct and intersecting pathways from glutamate and tau mediated toxicities specifically in the pyramidal neurons of
CA1 and CA3 regions of the hippocampus. Bacterial artificial chromosome TRAP (BAC-TRAP) reporter mouse lines in
conjunction with models of glutamate dyshomeostasis (EAAT2-/-) and mutant human tau (P301S) will be used to
generate translational profiles of CA1 and CA3 regions of the hippocampus at various stages of disease progression.
Further, we will also evaluate the role of EAAT2, the major glutamate transporter, in tau accumulation, trans synaptic
tau spread, immune dysfunction and neurodegeneration, and its potential as a therapeutic target using genetic (viral
vector) and chemical (riluzole) approaches. This proposal will provide novel insights into the molecular mechanisms of
excitatory neuronal susceptibility and resilience of inhibitory neurons in AD, identify potential new therapeutic targets for
tau-mediated neurodegeneration and provide a mechanistic understanding of glutamate transporter EAA...

## Key facts

- **NIH application ID:** 10092063
- **Project number:** 5R01AG063819-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ana C. Pereira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $777,842
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092063

## Citation

> US National Institutes of Health, RePORTER application 10092063, Mechanisms of Susceptibility of Excitatory Neurons to Tau Pathology and Neurodegeneration in Alzheimer's disease (5R01AG063819-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092063. Licensed CC0.

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