| First Author | Kumar P | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 2823 |
| PubMed ID | 38561349 | Mgi Jnum | J:348169 |
| Mgi Id | MGI:7619398 | Doi | 10.1038/s41467-024-47028-7 |
| Citation | Kumar P, et al. (2024) Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology. Nat Commun 15(1):2823 |
| abstractText | 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 Abeta pathology. PV-IN CIBOP in early stages of Abeta 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. |
