Soluble α-Synuclein Is a Novel Modulator of Alzheimer's Disease Pathophysiology

被引:114
|
作者
Larson, Megan E. [2 ,3 ]
Sherman, Mathew A. [2 ,3 ]
Greimel, Susan
Kuskowski, Michael [4 ]
Schneider, Julie A. [5 ]
Bennett, David A. [5 ]
Lesne, Sylvain E. [1 ,2 ,3 ]
机构
[1] Univ Minnesota, Inst Translat Neurosci Scholar, Dept Neurosci, Minneapolis, MN 55414 USA
[2] Univ Minnesota, N Bud Grossman Ctr Memory Res & Care, Minneapolis, MN 55414 USA
[3] Univ Minnesota, Inst Translat Neurosci, Minneapolis, MN 55414 USA
[4] VA Med Ctr, Geriatr Res Educ Clin Ctr, Minneapolis, MN 55417 USA
[5] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA
来源
JOURNAL OF NEUROSCIENCE | 2012年 / 32卷 / 30期
关键词
MILD COGNITIVE IMPAIRMENT; TRANSGENIC MOUSE MODEL; LEWY BODIES; PARKINSONS-DISEASE; A-BETA; OLIGOMERS; TAU; DEFICITS; AGGREGATION; BRAIN;
D O I
10.1523/JNEUROSCI.0581-12.2012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Recent evidence has emphasized soluble species of amyloid-beta (A beta) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that A beta, tau, and alpha-synuclein (alpha Syn) can promote each other's aggregation, the potential contribution of soluble alpha Syn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble alpha Syn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble alpha Syn levels were a quantitatively stronger correlate of cognitive impairment than soluble A beta and tau levels. To examine a putative role for alpha Syn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type alpha Syn. The results revealed that an approximate threefold elevation of alpha Syn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble alpha Syn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between A beta/APP and human tau seems to be responsible for the abnormal elevation of soluble alpha Syn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal alpha Syn in AD pathophysiology.
引用
收藏
页码:10253 / 10266
页数:14
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