Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques.
Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques.
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DOI：
10.1038/s41593-022-01084-8
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发表时间：
2022-06
影响因子：
25
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Lee, Ju-Hyun;Yang, Dun-Sheng;Goulbourne, Chris N.;Im, Eunju;Stavrides, Philip;Pensalfini, Anna;Chan, Han;Bouchet-Marquis, Cedric;Bleiwas, Cynthia;Berg, Martin J.;Huo, Chunfeng;Peddy, James;Pawlik, Monika;Levy, Efrat;Rao, Mala;Staufenbiel, Mathias;Nixon, Ralph A.
自噬在阿尔茨海默病（AD）中显著受损。在这里，我们揭示了独特的自噬失调神经元内的5个AD小鼠模型在体内，并确定其基础上使用神经元特异性的转基因mRFP-eGFP-LC 3探针的自噬和pH值，多重共聚焦成像和相关的光电子显微镜。早在细胞外淀粉样蛋白沉积之前，神经元中的自溶酶体酸化就下降了，这与vATPase活性显著降低和Aβ/APP-βCTF选择性地在扩大的去酸化自溶酶体内积聚有关。在受损较多但仍完整的神经元中，大量Aβ阳性自噬空泡（AV）填充成大的膜泡，形成花状核周突起。这种独特的模式，称为PANTHOS（有毒的花），也存在于AD大脑中。另外的AV合并成膜小管的核周网络，其中纤维状β-淀粉样蛋白在管腔内积聚。溶酶体膜透化，组织蛋白酶释放和溶酶体细胞死亡，伴随着小胶质细胞的侵袭。定量分析证实，表现PANTHOS的个体神经元是淀粉样前体蛋白AD模型中老年斑的主要来源。在阿尔茨海默氏病小鼠模型中，体内神经元自噬的研究发现，自体溶酶体酸化不足是极端自噬应激的基础，在完整神经元内产生β-淀粉样蛋白积累，这是老年斑的主要来源。
Autophagy is markedly impaired in Alzheimer’s disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models. Interrogation of neuronal autophagy in vivo in Alzheimerʼs disease mouse models identified deficient autolysosome acidification as the basis for extreme autophagic stress, yielding β-amyloid accumulation within intact neurons, which are the main source of senile plaques.
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影响因子：
5
作者：
Bach, G;Chen, CS;Pagano, RE
通讯作者：
Pagano, RE
影响因子：
4.6
作者：
Han S;Kollmer M;Markx D;Claus S;Walther P;Fändrich M
通讯作者：
Fändrich M
影响因子：
64.8
作者：
Janus, C;Pearson, J;Westaway, D
通讯作者：
Westaway, D
影响因子：
4
作者：
Esposito, Marcello;Dubbioso, Raffaele;Manganelli, Fiore
通讯作者：
Manganelli, Fiore
DOI：
10.1038/s41572-021-00269-y
发表时间：
2021-05-13
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Knopman DS;Amieva H;Petersen RC;Chételat G;Holtzman DM;Hyman BT;Nixon RA;Jones DT
通讯作者：
Jones DT