期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 23, 页码 E4648-E4657出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704698114
关键词
alpha-synuclein; oligomer; memory; Alzheimer's disease; synapsins
资金
- NIH [R01AG044342, 4185-9227-14, P30AG10161, R01AG15819]
- University of Minnesota Foundation
Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-beta (A beta), tau, or a-synuclein (alpha Syn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric alpha Syn species in AD brains by custom ELISA, size-exclusion chromatography, and non-denaturing/denaturing immunoblotting techniques. Importantly, the abundance of alpha Syn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human alpha Syn in an AD mouse model, we artificially enhanced alpha Syn oligomerization. These bigenic mice displayed exacerbated A beta-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble alpha Syn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric alpha Syn but not monomeric alpha Syn was causing a lowering in synapsin-I/II protein abundance. For a particular alpha Syn oligomer, these changes were either dependent or independent on endogenous alpha Syn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by alpha Syn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous alpha Syn oligomers can impair memory by selectively lowering synapsin expression.
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