We have located links that may give you full text access.
Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample.
Acta Neuropathologica 2021 March 2
Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app