Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age
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 cumulat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611830038X |
| _version_ | 1818352034406989824 |
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| author | Alfredo Ramos-Miguel Andrea A. Jones Ken Sawada Alasdair M. Barr Thomas A. Bayer Peter Falkai Sue E. Leurgans Julie A. Schneider David A. Bennett William G. Honer |
| author_facet | Alfredo Ramos-Miguel Andrea A. Jones Ken Sawada Alasdair M. Barr Thomas A. Bayer Peter Falkai Sue E. Leurgans Julie A. Schneider David A. Bennett William G. Honer |
| author_sort | Alfredo Ramos-Miguel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T18:47:13Z |
| format | Article |
| id | doaj.art-6f23767c581c41da940002d6280a8614 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:47:13Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-6f23767c581c41da940002d6280a86142022-12-21T23:35:02ZengElsevierNeurobiology of Disease1095-953X2018-06-011143144Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old ageAlfredo Ramos-Miguel0Andrea A. Jones1Ken Sawada2Alasdair M. Barr3Thomas A. Bayer4Peter Falkai5Sue E. Leurgans6Julie A. Schneider7David A. Bennett8William G. Honer9BC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, CanadaBC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, CanadaKochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, JapanBC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC V6T 1Z3, CanadaDepartment of Psychiatry, University Medicine Goettingen, von-Siebold-Strasse 5, D-37075 Goettingen, GermanyDepartment of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, D-80336 Munich, GermanyRush Alzheimer's disease Center, Rush University Medical Center, 600 S. Paulina Street, Chicago, IL 60612, United StatesRush Alzheimer's disease Center, Rush University Medical Center, 600 S. Paulina Street, Chicago, IL 60612, United StatesRush Alzheimer's disease Center, Rush University Medical Center, 600 S. Paulina Street, Chicago, IL 60612, United StatesBC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada; Corresponding author at: Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada.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.http://www.sciencedirect.com/science/article/pii/S096999611830038XSNARE complexProtein-protein interactionsNative PAGEPostmortem brainSynaptic pathologyAlzheimer's disease |
| spellingShingle | Alfredo Ramos-Miguel Andrea A. Jones Ken Sawada Alasdair M. Barr Thomas A. Bayer Peter Falkai Sue E. Leurgans Julie A. Schneider David A. Bennett William G. Honer Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age Neurobiology of Disease SNARE complex Protein-protein interactions Native PAGE Postmortem brain Synaptic pathology Alzheimer's disease |
| title | Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age |
| title_full | Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age |
| title_fullStr | Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age |
| title_full_unstemmed | Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age |
| title_short | Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age |
| title_sort | frontotemporal dysregulation of the snare protein interactome is associated with faster cognitive decline in old age |
| topic | SNARE complex Protein-protein interactions Native PAGE Postmortem brain Synaptic pathology Alzheimer's disease |
| url | http://www.sciencedirect.com/science/article/pii/S096999611830038X |
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