Journal ArticleNative-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathologyKumar, Prateek; Goettemoeller, Annie M; Espinosa-Garcia, Claudia; Tobin, Brendan R; Tfaily, Ali; Nelson, Ruth S; Natu, Aditya; Dammer, Eric B; Santiago, Juliet V; Malepati, Sneha; Cheng, Lihong; Xiao, Hailian; Duong, Duc D; Seyfried, Nicholas_T; Wood, Levi B; Rowan, Matthew_J_M; Rangaraju, Srikant<title>Abstract</title> <p>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.</p>Nature Communications/NCBI2024-04-0110525489Nature Communications1512041-1723https://doi.org/10.1038/s41467-024-47028-71944053Alzheimer's disease, proteomicsNational Science Foundation