Department of Pathology, Northwestern University, Illinois, USA.
Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Illinois, USA.
J Alzheimers Dis. 2023;92(1):241-260. doi: 10.3233/JAD-220848.
Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear.
To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer's Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD.
Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X.
Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization.
Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.
磷酸化细胞tau 包含物与阿尔茨海默病（AD）的认知缺陷相关，并先于认知缺陷出现。然而，病理性 tau 积累与突触变化之间的关系仍不清楚。
为了解决这一问题，我们检查了 50 名具有 AD 全谱（临床和神经病理学）的个体的死后大脑。在两个脑区（内嗅皮质和中额皮质）以及临床分层组（对照、遗忘型轻度认知障碍、AD 痴呆）、NIA-AA 阿尔茨海默病神经病理变化设计（无、低、中、高）和 Braak 缠结阶段（1-6）中比较了总 tau、pTau231 和 AMPA GluR1。排除显著共存的病理学以分离归因于病理性 AD 的变化。
通过突触小体分离和染色来测量总 Tau、pTau231 和 AMPA GluR1 的变化。使用 Quanterix Simoa HD-X 在突触小体部分中定量总 Tau 和 pTau231。
额叶突触后部分中 pTau231 的增加与临床和神经病理学 AD 严重程度的增加呈正相关。额叶皮质代表早期 AD，因为它直到 AD 的晚期才会被 tau 缠结累及。与 AD 相比，遗忘型轻度认知障碍组的内嗅皮质总 tau 明显升高，但仅在考虑到与 AD 相关的突触变化后才如此。在内嗅皮质中观察到的 AMPA GluR1 的改变，但在中额皮质中没有，这表明 pTau231 在突触后结构中的定位和聚集错误可能通过促进 AMPA 受体去磷酸化和内化来损害谷氨酸能信号传导。
结果强调了靶向突触后密度中 pTau231 积累的早期药物干预的潜在效果。
