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

BackgroundPresynaptic 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.ResultsUsing 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.ConclusionsM18L 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0061-4) contains supplementary material, which is available to authorized users.

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

“…Co-immunoprecipitation (IP) and Western blotting (WB) were used in characterization experiments as described elsewhere [36]. Subcellular extractions yielding proteins enriched in (1) nuclear- (along with cell debris), (2) cysosolic-, (3) membrane-, (4) synaptosomal- and (5) myelin-associated compartments were performed as reported [18, 36].…”

“…Subcellular extractions yielding proteins enriched in (1) nuclear- (along with cell debris), (2) cysosolic-, (3) membrane-, (4) synaptosomal- and (5) myelin-associated compartments were performed as reported [18, 36]. …”

“…To examine the contribution of complexins I and II to cognition, the adjusted R 2 values in the reference models containing the covariates and no target predictors were subtracted from the adjusted R 2 values in models including the predictor(s). Colocalization analyses between presynaptic proteins, or Aβ were performed with ImageJ 2.0 (NIH, Bethesda, MA, USA), using built-in unbiased algorithms [14, 36, 37]. For within-animal comparisons of complexins I and II colocalization with VGAT versus VGLUT1, data were analyzed with paired t -tests.…”

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

“…Indeed, a correlation was observed between the numbers of these interneurons and the apoptotic marker caspase-3 [ 226 ]. In another recent study, it was found that a long variant of the Munc18-1 protein (M18L) is important for presynaptic GABA function, and that expression of this protein is reduced in the AD frontal cortex [ 227 ]. The extent of this loss seemed to be correlated with greater cognitive decline and more severe AD pathology, and a statistical regression model suggested that M18L loss was correlated with a higher likelihood of developing dementia.…”

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells

“…However, other neuropathological processes are likely to contribute to the dysfunctional E/I network balance in the hippocampus that leads to cognitive deterioration. Although cognitive decline in AD has been largely related to Aβ oligomers and the glutamatergic system through multiple interactions [31,32], there is growing evidence to suggest that cognitive decline in the AD brain is influenced and also partly precipitated by altered GABAergic function [19], and this has been linked to cognitive decline [33]. In the extrasynaptic space, Aβ 1-42 mediates increase in ambient GABA levels which chronically activates tonic inhibitory currents in the hippocampus, that are involved in the maintenance of the excitatory network and synchronization, and in turn might contribute to the cognitive deficits -but the exact mechanism requires further elucidation.…”