Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.
Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.
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AP-4 复合物功能丧失导致的轴突细胞器堆积导致阿尔茨海默病小鼠模型中淀粉样斑块病理和神经胶质增生的恶化。
DOI：
10.1101/2024.03.31.587499
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Gowrishankar,Swetha
中科院分区：
文献类型：
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作者：
Orlowski,Alex;Karippaparambil,Joseph;Paumier,Jean-Michel;Ghanta,Shraddha;Pallares,Eduardo;Tandukar,Jamuna;Gao,Ruixuan;Gowrishankar,Swetha
溶酶体和相关的前体细胞器在围绕淀粉样斑块的肿胀轴突中大量积聚，并扰乱轴突溶酶体运输，与阿尔茨海默病的病理恶化有关。我们先前的研究表明，主要与痉挛性截瘫(HSP)有关的接头蛋白-4(AP-4)复合体功能的丧失，会导致结构中类似的溶酶体构建，我们称之为AP-4营养不良。令人惊讶的是，这些AP-4营养不良症的特征还包括APP处理机制、β位点裂解酶1和早老素2的丰富组件。我们的研究考察了AP-4缺失导致的轴突溶酶体异常积聚是否会导致淀粉样变的发生，结果显示，在阿尔茨海默病模型中，AP-4复合体功能的丧失导致海马体和胼胝体中淀粉样斑块的大小和丰富程度显著增加，以及与斑块的小胶质联系增加。有趣的是，我们发现与具有正常AP-4复合体功能的阿尔茨海默病模型小鼠相比，缺乏AP-4复合体的阿尔茨海默病模型小鼠的轴突肿胀中分泌酶BACE1的含量进一步增加，这表明在这种情况下淀粉样蛋白的形成过程增加。此外，斑块病理的恶化是区域性的，因为它不会在皮质增加。与皮质相比，与AP-4相关的轴突营养不良/AP-4营养不良在胼胝体和海马区的负荷更高，这确立了AP-4依赖的轴突溶酶体运输和成熟在调节淀粉样变性淀粉样前体蛋白加工中的关键作用。
Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to spastic paraplegia (HSP), leads to a similar build of lysosomes in structures we term “AP-4 dystrophies.” Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome buildup resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared with those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared with the cortex, establishing the critical role of AP-4-dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.