Saturday, May 17, 2025
5/17/2025
Multidimensional mapping of vulnerable cell types in humanized Alzheimer's disease mouse models - 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.
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