Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age

NEUROBIOLOGY OF DISEASE

卷:114

Article

Ramos-Miguel, Alfredo^1,2  Jones, Andrea A.^1,2  Sawada, Ken³  Barr, Alasdair M.^1,4  Bayer, Thomas A.⁵  Falkai, Peter⁶  Leurgans, Sue E.⁷  Schneider, Julie A.⁷  Bennett, David A.⁷  Honer, William G.^1,2 

[1] BC Mental Hlth & Addict Res Inst, 938 West 28th Ave, Vancouver, BC V5Z 4H4, Canada

[2] Univ British Columbia, Dept Psychiat, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada

[3] Kochi Med Sch, Oko Cho, Nankoku, Kochi 7838505, Japan

[4] Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, 2176 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada

[5] Univ Med Goettingen, Dept Psychiat, von Siebold Str 5, D-37075 Gottingen, Germany

[6] Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Nussbatanstr 7, D-80336 Munich, Germany

[7] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, 600 S Paulina St, Chicago, IL 60612 USA

关键词: SNARE complex;    Protein-protein interactions;    Native PAGE;    Postmortem brain;    Synaptic pathology;    Alzheimer's disease;    Cognitive decline;    Excitatory/inhibitory balance;    Aging;    Double dissociation;   

DOI  :  10.1016/j.nbd.2018.02.006

来源: Elsevier

【 摘 要 】

The molecular underpinnings associated with cognitive reserve remain poorly understood. Because animal models fail to fully recapitulate the complexity of human brain aging, postmortem studies from well-designed cohorts are crucial to unmask mechanisms conferring cognitive resistance against cumulative neuropathologies. We tested the hypothesis that functionality of the SNARE protein interactome might be an important resilience factor preserving cognitive abilities in old age. Cognition was assessed annually in participants from the Rush Memory and Aging Project (MAP), a community-dwelling cohort representative of the overall aging population. Associations between cognition and postmortem neurochemical data were evaluated in functional assays quantifying various species of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery in samples from the inferior temporal (IT, n = 154) and middle-frontal (MF, n = 174) gyri. Using blue-native gel electrophoresis, we isolated and quantified several types of complexes containing the three SNARE proteins (syntaxin-1, SNAP25, VAMP), as well as the GABAergic/glutamatergic selectively expressed complexins-I/II (CPLX1/2), in brain tissue homogenates and reconstitution assays with recombinant proteins. Multivariate analyses revealed significant associations between IT and MF neurochemical data (SNARE proteins and/or complexes), and multiple age-related neuropathologies, as well as with multiple cognitive domains of MAP participants. Controlling for demographic variables, neuropathologic indices and total synapse density, we found that temporal 150-kDa SNARE species (representative of pan-synaptic functionality) and frontal CPLX1/CPLX2 ratio of 500-kDa heteromeric species (representative of inhibitory/excitatory input functionality) were, among all the immunocharacterized complexes, the strongest predictors of cognitive function nearest death. Interestingly, these two neurochemical variables were associated with different cognitive domains. In addition, linear mixed effect models of global cognitive decline estimated that both 150-kDa SNARE levels and CPLX1/CPLX2 ratio were associated with better cognition and less decline over time. The results are consistent with previous studies reporting that synapse dysfunction (i.e. dysplasticity) may be initiated early, and relatively independent of neuropathology-driven synapse loss. Frontotemporal dysregulation of the GABAergic/glutamatergic stimuli might be a target for future drug development.

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