Changes in glial cell phenotypes precede overt neurofibrillary tangle formation, correlate with markers of cortical cell damage, and predict cognitive status of individuals at Braak III-IV stages.
Changes in glial cell phenotypes precede overt neurofibrillary tangle formation, correlate with markers of cortical cell damage, and predict cognitive status of individuals at Braak III-IV stages.
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DOI：
10.1186/s40478-022-01370-3
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发表时间：
2022-05-09
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
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作者：
临床病理相关性研究表明，一些从未发展认知障碍的健康老年人患有阿尔茨海默病病变（斑块和缠结），预计会导致痴呆。在没有解释这种差异的合并症的情况下，有必要确定其他大脑变化，这些变化有意义地有助于个体在面对斑块和缠结的这种负担时的认知状态。神经胶质炎性反应是症状性AD中的普遍现象，显示出与认知障碍程度的强相关性，但其在早期tau病理学阶段的意义以及对个体水平认知下降轨迹的贡献仍广泛未被探索。我们研究了55个大脑的个体在中间阶段的tau缠结病理（Braak III-IV）与不同的死前认知（痴呆与非痴呆，这里称为“顺从”），和年龄匹配的认知正常对照（Braak 0-II）。我们使用基于人工智能的半自动量化对颞极（Braak III-IV区）和视觉皮层（Braak V-VI区）的淀粉样蛋白和tau病变、细胞易损性标志物和神经胶质表型进行了定量评估。我们发现不同的神经胶质反应增加促炎和减少稳态标志物，无论是在区域与tau缠结（颞极）和没有明显的tau沉积（视觉皮层）在痴呆症，但不是在弹性。这些变化与皮质细胞损伤的标志物显著相关。类似的表型神经胶质细胞的变化被检测到的白色物质的痴呆症，但没有弹性，并与较高的负担，覆盖皮质细胞损伤的区域和无缠结。我们的数据表明，皮质和皮质下区域的胶质细胞表型的变化代表了明显的tau沉积之前的早期现象，并可能导致细胞损伤和脑功能丧失，预测个体在tau聚集负荷的中间阶段的认知状态（Braak III-IV）。
Clinico-pathological correlation studies show that some otherwise healthy elderly individuals who never developed cognitive impairment harbor a burden of Alzheimer’s disease lesions (plaques and tangles) that would be expected to result in dementia. In the absence of comorbidities explaining such discrepancies, there is a need to identify other brain changes that meaningfully contribute to the cognitive status of an individual in the face of such burdens of plaques and tangles. Glial inflammatory responses, a universal phenomenon in symptomatic AD, show robust association with degree of cognitive impairment, but their significance in early tau pathology stages and contribution to the trajectory of cognitive decline at an individual level remain widely unexplored. We studied 55 brains from individuals at intermediate stages of tau tangle pathology (Braak III-IV) with diverging antemortem cognition (demented vs. non-demented, here termed `resilient’), and age-matched cognitively normal controls (Braak 0-II). We conducted quantitative assessments of amyloid and tau lesions, cellular vulnerability markers, and glial phenotypes in temporal pole (Braak III-IV region) and visual cortex (Braak V-VI region) using artificial-intelligence based semiautomated quantifications. We found distinct glial responses with increased proinflammatory and decreased homeostatic markers, both in regions with tau tangles (temporal pole) and without overt tau deposits (visual cortex) in demented but not in resilient. These changes were significantly associated with markers of cortical cell damage. Similar phenotypic glial changes were detected in the white matter of demented but not resilient and were associated with higher burden of overlying cortical cellular damage in regions with and without tangles. Our data suggest that changes in glial phenotypes in cortical and subcortical regions represent an early phenomenon that precedes overt tau deposition and likely contributes to cell damage and loss of brain function predicting the cognitive status of individuals at intermediate stages of tau aggregate burden (Braak III-IV).
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影响因子：
7.1
作者：
Bachstetter AD;Van Eldik LJ;Schmitt FA;Neltner JH;Ighodaro ET;Webster SJ;Patel E;Abner EL;Kryscio RJ;Nelson PT
通讯作者：
Nelson PT
DOI：
10.1186/s13195-021-00880-x
发表时间：
2021-08-12
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Biel D;Brendel M;Rubinski A;Buerger K;Janowitz D;Dichgans M;Franzmeier N;Alzheimer’s Disease Neuroimaging Initiative (ADNI)
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
光学成像。膨胀显微镜。
DOI：
10.1126/science.1260088
发表时间：
2015-01-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen F;Tillberg PW;Boyden ES
通讯作者：
Boyden ES
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group