Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer's Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers.
Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer's Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers.
复制标题
DOI：
10.3233/jad-200716
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Taglialatela G
中科院分区：
文献类型：
--
作者：
Singh A;Allen D;Fracassi A;Tumurbaatar B;Natarajan C;Scaduto P;Woltjer R;Kayed R;Limon A;Krishnan B;Taglialatela G
某些个体，这里被称为非痴呆阿尔茨海默病神经病理学患者 (NDAN)，没有表现出明显的神经变性 (N-)，并且尽管存在通常与完全症状性阿尔茨海默病 (AD) 一致的斑块 (A+) 和缠结 (T+)，但认知能力保持完整。 NDAN (A + T+N-) 受试者的存在表明，人脑利用内在机制可以自然地避免通常与 AD 症状阶段相关的认知衰退 (A + T+N+)。破译其潜在机制将有助于开发补充疗法，以防止 AD 相关认知能力下降的进展。此前，我们曾报道过 NDAN 具有保留的神经发生和突触完整性，同时突触处不存在淀粉样蛋白寡聚体。使用年龄匹配的对照受试者、痴呆 AD 患者和 NDAN 个体的死后脑样本，我们进行了免疫荧光、蛋白质印迹、爪蟾卵母细胞突触膜微移植，然后进行双电极电压钳电生理学和荧光辅助单突触体长期增强研究。我们报告 NDAN 受试者大脑突触处的 tau 寡聚体减少。此外，我们使用新方法首次报告，与痴呆 AD 患者相比，NDAN 受试者突触中 tau 寡聚体的缺失与突触功能完整性相关。总体而言，这些结果进一步证实了 tau 寡聚体是突触破坏的主要作用者，强调了 AD 中的认知死亡，并支持其作为 AD 和相关 tau 病的可行治疗策略。
Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N-) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer’s disease (AD). The existence of NDAN (A + T+N-) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A + T+N+). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline. Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies. We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients. Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.