Selective lowering of synapsins induced by oligomeric ?-synuclein exacerbates memory deficits.

Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-? (A?), tau, or ?-synuclein (?Syn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric ?Syn species in AD brains by custom ELISA, ...
size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of ?Syn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human ?Syn in an AD mouse model, we artificially enhanced ?Syn oligomerization. These bigenic mice displayed exacerbated A?-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble ?Syn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric ?Syn but not monomeric ?Syn was causing a lowering in synapsin-I/II protein abundance. For a particular ?Syn oligomer, these changes were either dependent or independent on endogenous ?Syn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by ?Syn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous ?Syn oligomers can impair memory by selectively lowering synapsin expression.
Mesh Terms:
Alzheimer Disease, Animals, Brain, Cognition, Cyclic AMP Response Element-Binding Protein, Disease Models, Animal, Genes, Tumor Suppressor, Humans, Memory Disorders, Mice, Mice, Transgenic, Nuclear Proteins, Nuclear Receptor Subfamily 4, Group A, Member 2, Protein Structure, Quaternary, Recombinant Proteins, Solubility, Synapsins, alpha-Synuclein
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 06, 2016
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