Selective lowering of synapsins induced by oligomeric \u3b1-synuclein exacerbates memory deficits

Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-\u3b2 (A\u3b2), tau, or \u3b1-synuclein (\u3b1Syn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric \u3b1Syn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of \u3b1Syn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human \u3b1Syn in an AD mouse model, we artificially enhanced \u3b1Syn oligomerization. These bigenic mice displayed exacerbated A\u3b2-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble \u3b1Syn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric \u3b1Syn but not monomeric \u3b1Syn was causing a lowering in synapsin-I/II protein abundance. For a particular \u3b1Syn oligomer, these changes were either dependent or independent on endogenous \u3b1Syn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by \u3b1Syn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous \u3b1Syn oligomers can impair memory by selectively lowering synapsin expression