# Cell type vulnerability to pathogenic tau accumulation in hippocampal CA1

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $408,638

## Abstract

Alzheimer’s disease (AD) and other neurodegenerative diseases will have a global impact on health outcomes
for people in the coming decades. Without a cure or preventative treatment, it is likely that the economic costs
to the U.S. and other countries will be prohibitive, with estimates in the billions of dollars. Thus, understanding
the pathophysiology of the disease process will be integral for future therapeutic treatments. The presence of
senile plaques and neurofibrillary tangles (NFTs) are hallmarks of Alzheimer’s disease (AD). However, only
NFTs have been shown to correlate with the severity of the associated dementia. NFTs have been shown to
consist of aggregates of phosphorylated tau protein. Tau normally functions to stabilize microtubules in
neuronal processes, but in diseased brain cells tau becomes part of insoluble multi-protein NFT complexes as
well as soluble pathogenic oligomers. The progression of the disease follows a well described path initially
displaying NFT-associated neurodegeneration in a brain region called the entorhinal cortex followed by
neurodegeneration in a downstream brain region - the hippocampus. Importantly, these brain regions are
crucial for the formation of long-term memories and are likely responsible for the memory loss observed in AD
patients. This proposal will investigate the effect of trans-synaptic spread of pathogenic tau from entorhinal
cortical neurons to downstream neurons in the hippocampus. Our preliminary evidence demonstrates that not
all neurons in the hippocampus accumulate pathogenic tau and that specific subtypes of neurons in the
hippocampus are particularly vulnerable. The experimental design will involve adeno-associated viral vector
transfection, immunofluorescence to monitor tau trans-synaptic spread, and the use of cellular
electrophysiology to assess the impact that pathogenic tau spread has on vulnerable hippocampal neurons.
Importantly, we will also determine the effect of pathogenic tau on network properties of CA1 pyramidal
neurons when tau is expressed in select vulnerable neurons. By understanding the resultant changes
produced by pathogenic tau at the cellular and network level, it may be possible to develop therapies to
counteract these changes at early stages of AD.

## Key facts

- **NIH application ID:** 10985635
- **Project number:** 1R21AG085555-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** ADAM RORY MCQUISTON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,638
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985635

## Citation

> US National Institutes of Health, RePORTER application 10985635, Cell type vulnerability to pathogenic tau accumulation in hippocampal CA1 (1R21AG085555-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985635. Licensed CC0.

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