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PLD3影响阿尔茨海默病的轴突球状体和网络缺陷
2022-12-04 19:19

美国耶鲁大学Jaime Grutzendler团队发现,PLD3影响阿尔茨海默病的轴突球状体和网络缺陷。相关论文于2022年11月30日在线发表在《自然》杂志上。

研究人员确定淀粉样蛋白相关的轴突球状体是神经网络功能障碍的突出贡献者。通过使用眼底钙和电压成像,研究人员表明阿尔茨海默病的小鼠模型显示出长距离轴突连接的严重破坏。这种破坏是由动作电位传导阻断引起的,而动作电位传导阻断是由球状体的增大作为电流池的大小决定的。球状体的生长与年龄相关的大型内体性溶酶体小泡的积累有关,并与Pld3(一个潜在的阿尔茨海默病相关的风险基因)有关,该基因编码一种溶酶体蛋白,并在轴突球状体中高度富集。神经元过量表达Pld3导致内体性溶酶体囊泡积聚和球状体增大,从而加剧了轴突传导阻滞。

相比之下,Pld3的缺失减少了内体性溶酶体囊泡和球状体的大小,导致电传导和神经网络功能的改善。因此,有针对性地调节神经元内体性溶酶体的生物生成,有可能扭转阿尔茨海默病中轴突球状体引起的神经回路异常,这与淀粉样物质的去除无关。

据悉,导致阿尔茨海默病认知能力下降的确切机制尚不清楚。

附:英文原文

Title: PLD3 affects axonal spheroids and network defects in Alzheimer’s disease

Author: Yuan, Peng, Zhang, Mengyang, Tong, Lei, Morse, Thomas M., McDougal, Robert A., Ding, Hui, Chan, Diane, Cai, Yifei, Grutzendler, Jaime

Issue&Volume: 2022-11-30

Abstract: The precise mechanisms that lead to cognitive decline in Alzheimer’s disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction. Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner. Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3—a potential Alzheimer’s-disease-associated risk gene1 that encodes a lysosomal protein2,3 that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid removal.

DOI: 10.1038/s41586-022-05491-6

Source: https://www.nature.com/articles/s41586-022-05491-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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