Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer's disease neuropathologic change.
Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer's disease neuropathologic change.
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DOI：
10.1007/s00401-022-02526-0
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发表时间：
2023-03
影响因子：
12.7
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病（AD）不同阶段的个体表现出异常的脑电图活动，这与网络过度兴奋和认知能力下降有关。然而，在AD早期受影响的脑区中是否观察到突触水平的促兴奋变化，以及它们是否在MCI中出现，尚不清楚。同样重要的是，尚不清楚整体突触E/I失衡是否与AD连续体中认知障碍的严重程度相关。测量从认知正常、轻度认知受损和AD个体的海马和颞叶皮层微移植到替代细胞中的人类兴奋性和抑制性突触受体的离子电流幅度，我们发现兴奋性与抑制性（E/I）电流比率的前兴奋性变化的区域差异与毒性蛋白和病理程度正相关，并对认知表现分数产生负面影响。使用这些数据与电生理锚定分析在同一个人的突触蛋白质组，我们确定了一组蛋白质维持突触功能和突触毒性相关。我们还发现，颞叶皮层GABA能信号传导蛋白的功能和表达之间存在解偶联，这是E/I较大和认知能力较差的基础。进一步分析转录组和原位杂交数据集从一个独立的队列在整个连续的AD确认区域差异的E/I平衡，与最近校准的记忆，执行功能，语言和视觉空间能力，以及整体认知表现的综合评分呈负相关的前兴奋性变化。这些结果表明，早期的E/I平衡的变化可能有助于AD临床综合征的连续性认知能力的丧失。在线版本包含补充材料，可通过10.1007/s 00401 -022-02526-0获得。
Individuals at distinct stages of Alzheimer’s disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes at the synaptic level are observed in brain areas affected early in AD, and if they are emergent in MCI, is not clearly known. Equally important, it is not known whether global synaptic E/I imbalances correlate with the severity of cognitive impairment in the continuum of AD. Measuring the amplitude of ion currents of human excitatory and inhibitory synaptic receptors microtransplanted from the hippocampus and temporal cortex of cognitively normal, mildly cognitively impaired and AD individuals into surrogate cells, we found regional differences in pro-excitatory shifts of the excitatory to inhibitory (E/I) current ratio that correlates positively with toxic proteins and degree of pathology, and impinges negatively on cognitive performance scores. Using these data with electrophysiologically anchored analysis of the synapto-proteome in the same individuals, we identified a group of proteins sustaining synaptic function and those related to synaptic toxicity. We also found an uncoupling between the function and expression of proteins for GABAergic signaling in the temporal cortex underlying larger E/I and worse cognitive performance. Further analysis of transcriptomic and in situ hybridization datasets from an independent cohort across the continuum of AD confirm regional differences in pro-excitatory shifts of the E/I balance that correlate negatively with the most recent calibrated composite scores for memory, executive function, language and visuospatial abilities, as well as overall cognitive performance. These findings indicate that early shifts of E/I balance may contribute to loss of cognitive capabilities in the continuum of AD clinical syndrome. The online version contains supplementary material available at 10.1007/s00401-022-02526-0.
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影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1016/j.jalz.2017.04.011
发表时间：
2017-12
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Crane PK;Trittschuh E;Mukherjee S;Saykin AJ;Sanders RE;Larson EB;McCurry SM;McCormick W;Bowen JD;Grabowski T;Moore M;Bauman J;Gross AL;Keene CD;Bird TD;Gibbons LE;Mez J;Executive Prominent Alzheimer's Disease: Genetics and Risk Factors (EPAD:GRF) Investigators
通讯作者：
Executive Prominent Alzheimer's Disease: Genetics and Risk Factors (EPAD:GRF) Investigators
影响因子：
7.8
作者：
Fernandez-Perez EJ;Muñoz B;Bascuñan DA;Peters C;Riffo-Lepe NO;Espinoza MP;Morgan PJ;Filippi C;Bourboulou R;Sengupta U;Kayed R;Epsztein J;Aguayo LG
通讯作者：
Aguayo LG
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
15.1
作者：
Bjorklund NL;Reese LC;Sadagoparamanujam VM;Ghirardi V;Woltjer RL;Taglialatela G
通讯作者：
Taglialatela G