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Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample

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Abstract

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.

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Acknowledgements

We wish to express our gratitude to all participants in ROS/MAP, and to the staff in Rush Alzheimer's Disease Center. We also thank Hong-Ying Li and Jenny Yang for their skillful technical assistance. The study was supported by the Spanish Ministry of Science, Innovation and Universities (MCIU) and the European Regional Development Fund (ERDF) (grant RTI2018-094414-A-I00), the Canadian Institutes of Health Research (grant MOP-14037), and the U.S. National Institute of Health (grant U01 AG046152) and Aging (grant K23AG058752). ROS and MAP are collaborative, multidisciplinary, and translational research project funded by the National Institute on Aging (grants R01AG17917, R01AG42210). Dr Ramos-Miguel is a ‘Ramón y Cajal’ Researcher (grant RYC-2016-19282, MCIU-EHU/UPV).

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Authors and Affiliations

  1. Department of Pharmacology, University of the Basque Country (EHU/UPV) and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barrio Sarriena S/N, 48940, Leioa, Spain

    Alfredo Ramos-Miguel

  2. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

    Alfredo Ramos-Miguel, Andrea A. Jones & William G. Honer

  3. BC Mental Health and Substance Use Services Research Institute, Vancouver, BC, Canada

    Andrea A. Jones, Vilte E. Barakauskas, Alasdair M. Barr & William G. Honer

  4. Pacific Northwest National Laboratory, Richland, WA, USA

    Vladislav A. Petyuk

  5. Department of Anesthesia, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada

    Alasdair M. Barr

  6. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    Sue E. Leurgans, Julie A. Schneider & David A. Bennett

  7. Center for Translational and Computational Neuroimmunology, Department of Neurology and The Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Philip L. De Jager

  8. Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Kaitlin B. Casaletto

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  1. Alfredo Ramos-Miguel
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  2. Andrea A. Jones
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  11. William G. Honer
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Contributions

All authors contributed to the study conception and design. DAB and JAS conceived ROS and MAP studies. DAB, JAS, and SEL collected and organized demographic and clinical data. JAS conducted neuropathologic assessments. AR-M, AMB, WGH, and VAP selected the protein targets and designed the peptides. VAP and PLDJ performed LC-SRM proteomic assays and provided with quantitative datasets of the peptide. AR-M and VEB carried out validation experiments and immunofluorescence assays. AAJ carried out network analyses. AR-M and WGH compiled all study datasets and performed exploratory analyses. KBC and SEL supervised statistical approaches. AR-M, together with WGH, AAJ, and KBC wrote the first draft of the manuscript. All authors discussed the study results and commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Alfredo Ramos-Miguel.

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Conflict of interest

Dr. Honer has received consulting fees or sat on paid advisory boards for: AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, Lundbeck, AbbVie, and Newron, and holds shares in Translational Life Sciences, AbCellera, and Eli Lilly. The Organizations cited above had no role on (and therefore did not influence) the design of the present study, the interpretation of results, and/or preparation of the manuscript. All other authors have no financial interest on the reported data and declare no potential conflict of interests.

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Ramos-Miguel, A., Jones, A.A., Petyuk, V.A. et al. Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample. Acta Neuropathol 141, 755–770 (2021). https://doi.org/10.1007/s00401-021-02282-7

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