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 biotin...

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Published in:Nature communications Vol. 15; no. 1; pp. 2823 - 26
Main Authors: Kumar, 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.04.2024
Nature Publishing Group
Nature Portfolio
Subjects:
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13/44
13/95
14/63
631/378/1689/1283
631/45/475
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Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid
Animals
Biotinylation
Cognitive ability
Cytoskeleton
Humanities and Social Sciences
Humans
Interneurons
Interneurons - metabolism
Mass spectrometry
Mass spectroscopy
Metabolism
Mice
Mice, Transgenic
Mitochondria
multidisciplinary
Neurodegenerative diseases
Neurotransmission
Parvalbumin
Parvalbumins - metabolism
Pathogenesis
Pathology
Proteins
Proteome - metabolism
Proteomes
Proteomics
Resilience
Science
Science (multidisciplinary)
TOR protein
Translation
β-Amyloid
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Native state proteomics of PV interneurons revealed unique molecular features of high translational and metabolic activity, and enrichment of Alzheimer’s risk genes. Early amyloid pathology exerted unique effects on mitochondria, mTOR signaling and neurotransmission in PV neurons.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-47028-7