Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99)
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DOI：
10.1523/jneurosci.0578-19.2019
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发表时间：
2019-07-03
影响因子：
5.3
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Jiang, Ying;Sato, Yutaka;Nixon, Ralph A.
溶酶体衰竭是许多先天性神经退行性疾病的发病机制的基础，并且是阿尔茨海默病（AD）发病机制的早期和进行性特征。在这里，我们报告，溶酶体功能障碍唐氏综合征（21三体），神经发育障碍和早发性AD的形式，需要额外的基因拷贝的淀粉样前体蛋白（APP），并特别介导的β切割羧基端片段的APP（APP-β CTF，C99）。在DS患者的原代成纤维细胞中，自噬和内吞底物的溶酶体降解选择性受损，导致其在扩大的自体溶酶体/溶酶体中蓄积。溶酶体pH值的直接测量揭示了一个显着的升高（0.6个单位）作为基础的LC 3营业额放缓和组织蛋白酶D和其他溶酶体水解酶的失活已知是不稳定的或活性较低的溶酶体pH值持续升高。通过将酸性纳米颗粒递送到溶酶体来使溶酶体pH值正常化可以改善溶酶体缺陷，而RNA测序分析排除了转录对水解酶下降的贡献。从DS的Ts 2小鼠模型培养的皮质神经元表现出与DS细胞中的溶酶体缺陷相似的溶酶体缺陷。用siRNA或BACE 1抑制降低APP表达逆转了成纤维细胞和神经元中的组织蛋白酶缺陷。从成年Ts 2小鼠中删除一个Bace 1等位基因在体内具有类似的拯救作用。DS中破坏溶酶体功能所需的内源性APP-β CTF的适度升高与散发性AD相关，其中APP-β CTF而非APP也升高。我们的研究结果扩展了证据表明，受损的溶酶体酸化驱动进行性溶酶体衰竭多种形式的AD。
Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer's disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the beta cleaved carboxy terminal fragment of APP (APP-beta CTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one Bace1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-beta CTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-beta CTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.