# Multidimensional mapping of vulnerable cell types in humanized Alzheimer's disease mouse models

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $2,354,412

## Abstract

ABSTRACT
Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and the aggregation of amyloid-b
(Ab) and tau. The selective vulnerability of different brain regions and some cell types to AD pathology has been
established. However, much remains unknown regarding the disease-relevant mechanisms underlying this
differential response. We have previously used single-cell transcriptomics to perform an unbiased
characterization of vulnerable and resistant neuronal subtypes in the human AD brain (19 excitatory and 24
inhibitory subtypes; ~490,000 nuclei, multi-region dataset). This characterization revealed early transcriptional
changes in inhibitory interneurons, particularly in a population expressing the receptor tyrosine kinase c-Kit.
Using our novel method to isolate by FACS and profile neuronal somas with tau aggregates, we also quantified
the susceptibility of 20 major neocortical neuronal subtypes to the formation of neurofibrillary tangles (NFTs).
Although interneurons proved generally resistant to NFT formation, they were not spared from death. Our work
in the human brain highlights the existence of shared and distinct Ab- and tau-associated pathogenic
mechanisms as well as the need for a multidimensional approach to characterizing vulnerability in AD. This
proposal seeks to further characterize cell type-specific signatures of vulnerability to Ab and tau proteinopathies
in newly developed knock-in (KI) humanized mouse models of AD. We will test the hypothesis that early changes
in specific populations of GABAergic inhibitory interneurons, including c-Kit cells, are associated with network
dysfunction, early protein aggregation, and cognitive deficits in humanized AD mouse models. To model
pathogenic interactions between Ab and tau, we will use mouse models expressing humanized Ab without or
with familial AD (FAD) mutations and mouse models expressing human MAPT without or with a mutation
associated with tauopathy. In Aim 1, we will apply combined single-cell RNA- and ATAC-seq to tau-bearing and
tau-free somas from mice characterized behaviorally and electrophysiologically by chronic EEG/EMG recordings
and by standard and machine learning-analyzed behavior. In Aim 2, we will use spatial multiomics with single-
cell and subcellular resolution to map cell-type-specific vulnerabilities and cell-cell interactions in relation to Ab
and tau proteinopathies. In Aim 3, we will determine if Ab and/or tau alter the molecular, cellular, and circuit
properties of vulnerable c-Kit interneurons. In all aims, we will integrate our multiomics and functional data and
compare our mouse and previously-generated human data to identify evolutionarily conserved or species-
specific cell type behaviors. The completion of these aims will provide a human disease-relevant, large-scale
multiomics dataset instrumental to unravelling the mechanisms of neurodegeneration associated with Ab and
tau proteinopathies.

## Key facts

- **NIH application ID:** 10667216
- **Project number:** 1R01AG082147-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Inma Cobos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,354,412
- **Award type:** 1
- **Project period:** 2023-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667216

## Citation

> US National Institutes of Health, RePORTER application 10667216, Multidimensional mapping of vulnerable cell types in humanized Alzheimer's disease mouse models (1R01AG082147-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10667216. Licensed CC0.

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