Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models
Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models
复制标题
DOI：
10.1074/jbc.m115.643577
复制
发表时间：
2015-07-10
影响因子：
4.8
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
--
作者：
Kostylev, Mikhail A.;Kaufman, Adam C.;Strittmatter, Stephen M.
阿尔茨海默病(AD)的特点是淀粉样β蛋白蓄积，其中可溶性寡聚体(Aβo)是最具突触毒性的。然而，Aβo的多价和不稳定性质限制了分子特征，并阻碍了研究的重复性。在这里，我们描述了在各种AD小鼠的整个生命周期和死后的人类大脑中的多种Aβo形式。Aβo存在于几个种群中，其中Prion蛋白(PrPC)相互作用的Aβo是一种高分子质量的Aβ组件，存在于多个AD小鼠和人类中。PrPC相互作用的Aβo水平与小鼠的记忆密切相关，在预测行为损害方面与其他Aβ指标持平或更好。然而，Aβo指标在不同品系的小鼠之间差别很大。在PrPC相互作用A beta o(Tg2576)相对较低的小鼠中，删除PrPC表达会导致认知能力的部分挽救，而不是PrPC相互作用A beta o(APP/PSEN1)比例较高的动物完全恢复。这些发现突出了Aβo形式在AD中的相对贡献和相互作用。
Alzheimer disease (AD) is characterized by amyloid-beta accumulation, with soluble oligomers (A beta o) being the most synaptotoxic. However, the multivalent and unstable nature of A beta o limits molecular characterization and hinders research reproducibility. Here, we characterized multiple A beta o forms throughout the life span of various AD mice and in post-mortem human brain. A beta o exists in several populations, where prion protein (PrPC)-interacting A beta o is a high molecular weight A beta assembly present in multiple mice and humans with AD. Levels of PrPC-interacting A beta o match closely with mouse memory and are equal or superior to other A beta measures in predicting behavioral impairment. However, A beta o metrics vary considerably between mouse strains. Deleting PrPC expression in mice with relatively low PrPC-interacting A beta o (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrPC-interacting A beta o (APP/PSEN1). These findings highlight the relative contributions and interplay of A beta o forms in AD.