title: Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer's disease.
abstract: Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P < 0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0-II, while excitatory complexin-II explained 7.3% of the variance in Braak V-VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.
authors.affiliation: BC 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.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramos-Miguel
authors.affiliation: Kochi Prefectural Aki General Hospital, 3-33 Hoheicho, Kochi, 784-0027, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sawada
authors.affiliation: BC 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.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Jones
authors.affiliation: BC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.|Department of Psychology, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada.
authors.forename: Allen E
authors.initials: AE
authors.lastname: Thornton
authors.affiliation: BC 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, Canada.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina Street, Chicago, IL, 60612, USA.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina Street, Chicago, IL, 60612, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina Street, Chicago, IL, 60612, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: BC Mental Health and Addictions Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. william.honer@ubc.ca.|Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. william.honer@ubc.ca.
authors.forename: William G
authors.initials: WG
authors.lastname: Honer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications*; D000818:Animals; D001344:Autopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012111:Residence Characteristics; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins; C493464:SLC17A7 protein, human; C492245:SLC32A1 protein, human; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C095992:complexin I; C095993:complexin II
keywords: Aging study; Braak staging; Cognitive decline; Dementia; Inhibitory terminals; Postmortem human brain; Synaptic pathology