Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer's disease.
Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer's disease.
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DOI：
10.1007/s00401-016-1647-9
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发表时间：
2017-03
影响因子：
12.7
通讯作者：
Honer WG
中科院分区：
文献类型：
--
作者：
Ramos-Miguel A;Sawada K;Jones AA;Thornton AE;Barr AM;Leurgans SE;Schneider JA;Bennett DA;Honer WG
阿尔茨海默病相关病理的逐渐积累与认知功能障碍有关。在存在可比较的神经病理学情况下，认知储备的差异可能会导致认知功能的个体差异。认知储备的保护作用在疾病的早期和晚期可能有所不同。我们研究了突触前蛋白作为大脑储备（总认知储备的一个子集）的衡量标准，并使用 Braak 分期来估计阿尔茨海默病的进展。一项社区研究中，对 418 名已故参与者的多个关键大脑区域进行了生前认知功能评估、死后病理指标评估和突触前蛋白质分析（包括分别作为抑制性和兴奋性终末功能测量的复合蛋白 I 和 II）。在人口统计学变量、病理指标和整体突触密度共变后，较低的大脑复合蛋白-I 和 -II 水平导致认知功能障碍（P < 0.01）。每种复合蛋白似乎在不同的布拉克阶段都失调。抑制性复合蛋白-I 解释了 Braak 0-II 中整体认知差异的 14.4%，而兴奋性复合蛋白-II 解释了 Braak V-VI 中 7.3% 的差异。与其他突触前蛋白不同，复合蛋白不与神经炎斑块内的病理性 tau 蛋白共定位，这表明突触机制的这些功能成分在营养不良的神经突中早期被清除。此外，在大鼠模型中，复合蛋白水平显示出与记忆挑战相关的独特变化模式，支持了这些蛋白质的功能特异性。目前的结果表明，抑制性突触末梢的破坏可能引发早期认知障碍，而兴奋性突触末梢的破坏可能相对更多地导致后期认知障碍。
Progressive accumulation of Alzheimer’s disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer’s disease. Antemortem evaluations of cognitive function, postmortem assessments of pathologic indices, and presynaptic protein analyses, including the complexins I and II as respective measures of inhibitory and excitatory terminal function, were assayed in multiple key brain regions in 418 deceased participants from a community study. After covarying for demographic variables, pathologic indices, and overall synapse density, lower brain complexin-I and -II levels contributed to cognitive dysfunction (P < 0.01). Each complexin appeared to be dysregulated at a different Braak stage. Inhibitory complexin-I explained 14.4% of the variance in global cognition in Braak 0-II, while excitatory complexin-II explained 7.3% of the variance in Braak V-VI. Unlike other presynaptic proteins, complexins did not colocalize with pathologic tau within neuritic plaques, suggesting that these functional components of the synaptic machinery are cleared early from dystrophic neurites. Moreover, complexin levels showed distinct patterns of change related to memory challenges in a rat model, supporting the functional specificity of these proteins. The present results suggest that disruption of inhibitory synaptic terminals may trigger early cognitive impairment, while excitatory terminal disruption may contribute relatively more to later cognitive impairment.
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影响因子：
4.2
作者：
Ball, M;Braak, H;Khachaturian, Z
通讯作者：
Khachaturian, Z
影响因子：
--
作者：
Begemann, Martin;Grube, Sabrina;Ehrenreich, Hannelore
通讯作者：
Ehrenreich, Hannelore
影响因子：
16.2
作者：
Bakker A;Krauss GL;Albert MS;Speck CL;Jones LR;Stark CE;Yassa MA;Bassett SS;Shelton AL;Gallagher M
通讯作者：
Gallagher M
影响因子：
4.8
作者：
Li Y;Sun H;Chen Z;Xu H;Bu G;Zheng H
通讯作者：
Zheng H
影响因子：
12.7
作者：
Koliatsos, Vassilis E.;Kecojevic, Aleksandar;Schneider, Julie A.
通讯作者：
Schneider, Julie A.