Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
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DOI：
10.1038/s41380-020-0806-5
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发表时间：
2021-10
影响因子：
11
通讯作者：
Nižetić D
中科院分区：
文献类型：
--
作者：
Alić I;Goh PA;Murray A;Portelius E;Gkanatsiou E;Gough G;Mok KY;Koschut D;Brunmeir R;Yeap YJ;O'Brien NL;Groet J;Shao X;Havlicek S;Dunn NR;Kvartsberg H;Brinkmalm G;Hithersay R;Startin C;Hamburg S;Phillips M;Pervushin K;Turmaine M;Wallon D;Rovelet-Lecrux A;Soininen H;Volpi E;Martin JE;Foo JN;Becker DL;Rostagno A;Ghiso J;Krsnik Ž;Šimić G;Kostović I;Mitrečić D;LonDownS Consortium;Francis PT;Blennow K;Strydom A;Hardy J;Zetterberg H;Nižetić D
全世界有超过600万人处于阿尔茨海默病（AD）的高风险人群是患有唐氏综合征（DS，由21三体（T21）引起）的人群，其中70%的人在一生中发展痴呆，这是由β-淀粉样蛋白（Aβ）-β受体蛋白基因的额外拷贝引起的。我们报告了从71%的DS供体的非侵入性采样头发中体外生长的脑类器官中的AD样病理学。病理学包括细胞外弥漫性和纤维状Aβ沉积、过度磷酸化/病理学证实的Tau和过早神经元丢失。AD样病理的存在/不存在是供体特异性的（在个体类器官/iPSC系/实验之间可再现）。在病理阴性的T21类器官中，可以通过CRISPR/Cas9介导的21号染色体基因BACE 2的第三拷贝的消除来触发病理，但是通过组合的化学β和γ-分泌酶抑制来预防。我们发现T21类器官分泌Aβ预防（Aβ1-19）和Aβ降解产物（Aβ1-20和Aβ1-34）的比例增加。我们在DS患者的脑脊液中显示了这些特征。我们证明了这种保护机制是由BACE 2-三体介导的，并被临床试验的BACE 1抑制剂交叉抑制。结合，我们的数据证明了BACE 2作为剂量敏感的AD抑制基因的生理作用，可能解释了约30%的DS患者的痴呆延迟。我们还表明，DS脑类器官可以作为疾病前AD风险人群检测器和无假设药物筛选系统以及神经退行性疾病天然抑制基因的鉴定进行探索。
A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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影响因子：
15.1
作者：
Abdul-Hay SO;Sahara T;McBride M;Kang D;Leissring MA
通讯作者：
Leissring MA
伴侣介导的自噬的时代的到来。
DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Kaushik S;Cuervo AM
通讯作者：
Cuervo AM
影响因子：
12.7
作者：
Mann DMA;Davidson YS;Robinson AC;Allen N;Hashimoto T;Richardson A;Jones M;Snowden JS;Pendleton N;Potier MC;Laquerrière A;Prasher V;Iwatsubo T;Strydom A
通讯作者：
Strydom A
影响因子：
11
作者：
Gonzalez C;Armijo E;Bravo-Alegria J;Becerra-Calixto A;Mays CE;Soto C
通讯作者：
Soto C
影响因子：
4
作者：
Deutsch, S;Choudhury, U;Antonarakis, SE
通讯作者：
Antonarakis, SE