Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases
Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases
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DOI：
10.1016/j.ajpath.2015.09.018
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发表时间：
2016-01-01
影响因子：
6
通讯作者：
Gylys, Karen H.
中科院分区：
文献类型：
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作者：
Bilousova, Tina;Miller, Carol. A.;Gylys, Karen H.
β 淀粉样蛋白 (A beta) 和过度磷酸化 tau (p-tau) 聚集体形成阿尔茨海默病 (AD) 的两种不同病理，每种蛋白质的寡聚体组装都定位于突触。为了确定突触中病理出现的顺序，对顶叶皮层 AD 疾病阶段的 A beta 和 p-tau 进行了定量。纳入具有高水平 AD 相关病理的非痴呆病例，以确定可防止临床症状的因素。使用突触体制剂的流式细胞术分析来量化大量个体突触末端中的 Aβ 和 p-tau。通过单抗体夹心酶联免疫吸附测定法对可溶性 Aβ 寡聚物进行测定。与年龄匹配的正常对照相比，早期和晚期 AD 痴呆患者的原位总 Aβ 升高，但在高度病理性非痴呆对照中则没有升高。然而，可溶性 Aβ 寡聚体在早期 AD 突触中最高，并且该测定将早期 AD 病例与高病理对照区分开来。总体而言，在人类和转基因大鼠皮层中，突触相关的 p-tau 直到疾病晚期才增加，并且在 AD 早期个体 Aβ 阳性突触体中 p-tau 升高。这些结果表明，幸存的新皮质突触末端中的可溶性寡聚体与痴呆症的发病有关，并提出了淀粉样蛋白级联假说，其中寡聚体 All 驱动磷酸化 tau 积累和突触扩散。这些结果表明，一旦出现 p-tau 病理学，抗淀粉样蛋白疗法的效果就会降低。
Amyloid-beta (A beta) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, A beta and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high Levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify A beta and p-tau in Large populations of individual synaptic terminals. Soluble A beta oligomers were assayed by a single antibody sandwich enzyme-Linked immunosorbent assay. Total in situ A beta was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble A beta oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until Late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual A beta-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric All drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.