title: Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample.
abstract: BACKGROUND
  Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer's disease pathology.
  
  
  RESULTS
  Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50-0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals.
  
  
  CONCLUSIONS
  M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.
authors.affiliation: Child and Family Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. alfredo.ramos@ubc.ca.|Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. alfredo.ramos@ubc.ca.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramos-Miguel
authors.affiliation: Child and Family Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. christahercher@yahoo.ca.|Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. christahercher@yahoo.ca.
authors.forename: Christa
authors.initials: C
authors.lastname: Hercher
authors.affiliation: Child and Family Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. cbeasley@mail.ubc.ca.|Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada. cbeasley@mail.ubc.ca.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Beasley
authors.affiliation: Child and Family Research Institute, 938 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. al.barr@ubc.ca.|Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. al.barr@ubc.ca.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
authors.affiliation: Department of Psychiatry, University Medicine Goettingen, von-Siebold-Strasse 5, D-37075, Goettingen, Germany. thomas.bayer@medizin.uni-goettingen.de.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, D-80336, Munich, Germany. peter.falkai@med.uni-muenchen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600S. Paulina Street, IL, 60612, Chicago, USA. Sue_E_Leurgans@rush.edu.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Leurgans
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600S. Paulina Street, IL, 60612, Chicago, USA. julie_a_schneider@rush.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, 600S. Paulina Street, IL, 60612, Chicago, USA. david_a_bennett@rush.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Child and Family 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: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D051938:Munc18 Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D051938:Munc18 Proteins