Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology.

Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation in Alzheimer's Disease (AD). Defining early proteomic alterations in PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. PV-IN proteomic signatures include high metabolic and translational activity, with over-representation of AD-risk and cognitive resilience-related proteins. In bulk proteomes, PV-IN proteins were associated with cognitive decline in humans, and with progressive neuropathology in humans and the 5xFAD mouse model of Aβ pathology. PV-IN CIBOP in early stages of Aβ pathology revealed signatures of increased mitochondria and metabolism, synaptic and cytoskeletal disruption and decreased mTOR signaling, not apparent in whole-brain proteomes. Furthermore, we demonstrated pre-synaptic defects in PV-to-excitatory neurotransmission, validating our proteomic findings. Overall, in this study we present native-state proteomes of PV-INs, revealing molecular insights into their unique roles in cognitive resiliency and AD pathogenesis. © 2024. The Author(s).

Citation

Prateek Kumar, Annie M Goettemoeller, Claudia Espinosa-Garcia, Brendan R Tobin, Ali Tfaily, Ruth S Nelson, Aditya Natu, Eric B Dammer, Juliet V Santiago, Sneha Malepati, Lihong Cheng, Hailian Xiao, Duc D Duong, Nicholas T Seyfried, Levi B Wood, Matthew J M Rowan, Srikant Rangaraju. Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology. Nature communications. 2024 Apr 01;15(1):2823

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PMID: 38561349

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