MIND Institute, Center for Neurobiology of Learning and Memory, Irvine, CA, USA.
Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
J Alzheimers Dis. 2020;73(1):229-246. doi: 10.3233/JAD-190835.
This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.
这项工作深入了解了阿尔茨海默病（AD）的年龄相关性基础、细胞内淀粉样蛋白（iAβ）的组成以及成年 AD 模型小鼠神经元中与年龄相关的 iAβ增加的机制。一种新的针对 Aβ45 的末端特异性抗体和另一种针对 Aβ聚集形式的抗体，为了解 iAβ的组成和在 3xTg-AD 模型小鼠老年神经元中积累的机制提供了新的见解。来自年轻到老年的神经元中，含有 Aβ45 聚集物的 iAβ水平增加了 30-50 倍，并且在谷氨酸处理后进一步受到刺激。3xTg-AD 中的 iAβ比非转基因神经元丰富 8 倍，成像后的颗粒大小遵循相同的对数-对数分布，表明存在类似的细胞内生物发生雪球机制。病理性错误折叠和定位错误的 Alz50 tau 与 iAβ共定位，并在经历短暂的代谢应激（谷氨酸）后迅速增加。AβPP-CTF、Aβ45 和聚集的 Aβ与线粒体和内体共定位最强，与溶酶体和自噬体共定位较弱。性别差异对 iAβ的影响较小。这些结果表明，γ-分泌酶对长 Aβ的羧基末端不完全修剪产生了大量细胞内沉积物，从而限制了老年神经元中自噬的完成。了解与年龄相关的 iAβ加工变化的机制可能会导致采取对策来延长无痴呆健康寿命。
