BACKGROUND: Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein @entity37809 , alternatively spliced into long ( @entity69029 ) or short ( @entity69030 ) isoforms, is a critical modulator of neurotransmission. While subtle alterations in @entity37809 have been shown to cause severe @entity146 with @entity73 , little information is known regarding the specific roles of @entity37809 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of @entity69029 and @entity69030 , and then evaluated their contribution to the full range of age-related @entity73 in the dorsolateral prefrontal cortex of a large sample of @entity1 from a community-based aging study, including subjects with no-(NCI, n   =   90), or mild-(MCI, n   =   86) @entity73 , or with clinical @entity303 (n   =   132). Finally, we used APP23 mutant @entity19 to study the association between @entity69029 /S and the time-dependent accumulation of common @entity195 pathology. RESULTS: Using isoform-specific antibodies, @entity69029 was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. @entity69030 was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified @entity69029 in perisomatic, GABAergic terminals, while @entity69030 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 @entity69029 (p   =   0.006) but not @entity69030 (p   =   0.88). Mean @entity69029 in @entity303 cases was 51  % lower than in NCI cases (p   <   0.001), and each unit of @entity69029 was associated with a lower likelihood of @entity303 (odds ratio   =   0.68, 95  % confidence interval   =   0.50-0.90, p   =   0.008). In contrast, @entity69030 balanced across clinical and pathologically diagnosed groups. @entity69029 loss may not be caused by age-related amyloid pathology, since APP23 @entity19 (12- and 22-months of age) had unchanged cortical levels of @entity69029 /S compared with wild-type animals. CONCLUSIONS: @entity69029 was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from @entity303 in an elderly, community-based cohort. Lower @entity69029 in inhibitory presynaptic terminals may be an early, independent contributor to @entity73 .

Loss of @entity37809 long splice variant in GABAergic terminals is associated with XXXX and increased risk of @entity303 in a community sample.

@entity1 :: ('9606', 'Species') :: ['participants'] @entity37809 :: ('20910(Tax:10090)', 'Gene') :: ['Munc18-1'] @entity146 :: ('MESH:D001523', 'Disease') :: ['neuropsychiatric disorders'] @entity303 :: ('MESH:D003704', 'Disease') :: ['dementia'] @entity73 :: ('MESH:D003072', 'Disease') :: ['cognitive impairment', 'cognitive decline'] @entity69030 :: ('p|SUB|M|18|S', 'ProteinMutation') :: ['M18S'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity69029 :: ('p|SUB|M|18|L', 'ProteinMutation') :: ['M18L'] @entity195 :: ('MESH:D000544', 'Disease') :: ["Alzheimer's disease"]
@entity73 :: (MESH:D003072,Disease) :: ['cognitive decline']
