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Clinical and synaptosomal studies of cannabinoid receptor 1 and presynaptic proteins in the elderly Alamri, Jehan Saleh


Neuroimaging and postmortem findings indicate loss and dysfunction of presynaptic terminals contribute to cognitive deterioration and depression in the elderly. However, the molecular mechanisms remain unclear. The contributions of presynaptic cannabinoid receptor 1 (CB1R) and calcium-sensing synaptotagmin- 1 (STG) isoforms to the pathologic burden, cognitive performance, and likelihood of depressive symptoms were investigated in older individuals from a community-based prospective study. Levels of CB1R and STG isoforms were quantified in middle frontal gyrus (n = 308) and hippocampus (n = 294) by immunoblotting. A possible link between CB1R and presynaptic proteins was investigated using coimmunoprecipitation assays and confocal microscopy. The role of calpain activity in cleavage of the 25 kDa synaptosomal-associated protein (SNAP-25) was studied in prefrontal cortical synaptosomes (n = 66). Findings indicated CB1R level was unchanged in both brain regions across pathologically and cognitively diagnosed groups. Linear regression models adjusting for demographics and age-related neuropathologies revealed that prefrontal cortical and hippocampal levels of CB1R were not associated with global cognitive function. Each unit increase of hippocampal CB1R level was associated with a lower likelihood of depressive symptoms. Presynaptic proteins were immunoprecipitated and colocalized with the CB1R. Immunoblotting detected full-length STG (65 kDa) and two fragments (47 kDa and 35 kDa). More severe tau pathology and poorer global cognitive function were associated with lower levels of hippocampal 35 kDa STG but not 65 kDa or 47 kDa STG. Greater amounts of 65 kDa STG only were associated with lower odds of depressive symptoms. No associations between pathology, cognition, or depression were observed for STG in prefrontal cortex. Higher synaptosomal calpain activity was not associated with SNAP-25 cleavage but demonstrated a complex relationship with the odds of clinical dementia. These findings suggest a role for the CB1R in altered presynaptic function in the elderly, isoform-specific effects of STG on cognition and depression in aging, and a possible link between calpain activity and dementia.

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