Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes
Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes
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DOI：
10.3233/jad-190835
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Glabe, Charles G.
中科院分区：
文献类型：
--
作者：
Brewer, Gregory J.;Herrera, Robert A.;Glabe, Charles G.
这项工作为阿尔茨海默病（AD）的年龄相关基础，神经元内淀粉样蛋白（iA β）的组成以及成年AD模型小鼠神经元中iA β年龄相关性增加的机制提供了新的见解。A β的一种新的末端特异性抗体（45）和A β聚集形式的另一种抗体为3xTg-AD模型小鼠的老年成年神经元中iA β的组成和积累机制提供了新的见解。含有A β聚集体的iA β水平（45）在神经元中从年轻到老年增加30-50倍，并且在谷氨酸处理后进一步刺激。iA β在3xTg-AD中的丰度是非转基因神经元的8倍，其成像颗粒大小遵循相同的对数-对数分布，表明细胞内生物发生的类似雪球机制。病理性错误折叠和错误定位的A1 z50 tau与iA β共定位，并在谷氨酸短暂代谢应激后迅速增加。A β PP-CTF、A β（45）和聚集的A β与线粒体和内体共定位最强，与溶酶体和自噬体共定位较少。不同性别的iA β差异较小。这些结果表明，不完全的羧基端修剪长A β的γ-分泌酶产生大的细胞内沉积物，限制了老年神经元自噬的完成。了解iA β处理中与年龄相关的变化机制可能会导致应用对策来延长无痴呆症的健康寿命。
This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA beta), and the mechanism of an age-related increase in iA beta in adult AD-model mouse neurons. A new end-specific antibody for A beta(45) and another for aggregated forms of A beta provide new insight into the composition of iA beta and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA beta levels containing aggregates of A beta(45) increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA beta 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 A1z50 tau colocalized with iA beta and rapidly increased following a brief metabolic stress with glutamate. A beta PP-CTF, A beta(45), and aggregated A beta colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA beta by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A beta s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA beta processing may lead to application of countermeasures to prolong dementia-free health span.