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OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.
EBioMedicine ( IF 11.1 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.ebiom.2019.11.030 Xuping Li 1 , Lin Wang 2 , Matthew Cykowski 3 , Tiancheng He 2 , Timothy Liu 1 , Joshua Chakranarayan 1 , Andreana Rivera 3 , Hong Zhao 1 , Suzanne Powell 3 , Weiming Xia 4 , Stephen T C Wong 5
EBioMedicine ( IF 11.1 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.ebiom.2019.11.030 Xuping Li 1 , Lin Wang 2 , Matthew Cykowski 3 , Tiancheng He 2 , Timothy Liu 1 , Joshua Chakranarayan 1 , Andreana Rivera 3 , Hong Zhao 1 , Suzanne Powell 3 , Weiming Xia 4 , Stephen T C Wong 5
Affiliation
BACKGROUND
Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD.
METHODS
Bioinformatics and experimental neurobiology methods were integrated to identify novel factors involved in the hyperamyloidosis-induced brain vulnerability in AD. We first examined neurodegeneration-specific gene signatures from sporadic AD patients and synaptic protein changes in young transgenic AD mice. Then, we systematically assessed the association of a top candidate gene with AD and investigated its mechanistic role in neurodegeneration.
FINDINGS
We identified the ovary-orientated protein OCIAD1 (Ovarian-Carcinoma-Immunoreactive-Antigen-Domain-Containing-1) as a neurodegeneration-associated factor for AD. Higher levels of OCIAD1, found in vulnerable brain areas and dystrophic neurites, were correlated with disease severity. Multiple early AD pathological events, particularly Aβ/GSK-3β signaling, elevate OCIAD1, which in turn interacts with BCL-2 to impair mitochondrial function and facilitates mitochondria-associated neuronal injury. Notably, elevated OCIAD1 by Aβ increases cell susceptibility to other AD pathological challenges.
INTERPRETATION
Our findings suggest that OCIAD1 contributes to neurodegeneration in AD by impairing mitochondria function, and subsequently leading to neuronal vulnerability, and synaptic damages.
FUNDING
Ting Tsung & Wei Fong Chao Foundation, John S Dunn Research Foundation, Cure Alzheimer's Fund, and NIH R01AG057635 to STCW.
中文翻译:
OCIAD1通过诱导线粒体功能障碍,神经元脆弱性和突触损伤,促进阿尔茨海默氏病的神经退行性变。
背景技术脑中的淀粉样变性病被称为阿尔茨海默氏病(AD)的最早的神经病理学改变和独特的病因,而某些脆弱的大脑区域中进行性神经变性则形成了临床综合征的基础。目前尚不清楚早期的超淀粉样变性病与进行性神经退行性疾病有何关系,以及哪些因素导致了AD选择性脑的易损性。方法整合了生物信息学和实验神经生物学方法,以鉴定与高淀粉样变性引起的AD的大脑易损性有关的新因素。我们首先检查了散发性AD患者的神经退行性特异性基因特征以及年轻的转基因AD小鼠的突触蛋白变化。然后,我们系统地评估了顶级候选基因与AD的关联,并研究了其在神经退行性变中的机制作用。结果我们确定了卵巢定向蛋白OCIAD1(卵巢癌-免疫反应-抗原-域-包含1)是AD的神经退行性相关因素。在脆弱的大脑区域和营养不良的神经突中发现的较高水平的OCIAD1与疾病严重程度相关。多个早期AD病理事件,尤其是Aβ/GSK-3β信号,升高了OCIAD1,OCIAD1反过来又与BCL-2相互作用,损害线粒体功能并促进线粒体相关的神经元损伤。值得注意的是,通过Aβ升高的OCIAD1可以增加细胞对其他AD病理学挑战的敏感性。解释我们的发现表明,OCIAD1通过损害线粒体功能,进而导致神经元脆弱性和突触损伤,促进了AD的神经变性。筹款Tsung Tsung和Wei Fong Chao基金会,John S Dunn研究基金会,Cure Alzheimer基金会和STCW的NIH R01AG057635。
更新日期:2020-01-11
中文翻译:
OCIAD1通过诱导线粒体功能障碍,神经元脆弱性和突触损伤,促进阿尔茨海默氏病的神经退行性变。
背景技术脑中的淀粉样变性病被称为阿尔茨海默氏病(AD)的最早的神经病理学改变和独特的病因,而某些脆弱的大脑区域中进行性神经变性则形成了临床综合征的基础。目前尚不清楚早期的超淀粉样变性病与进行性神经退行性疾病有何关系,以及哪些因素导致了AD选择性脑的易损性。方法整合了生物信息学和实验神经生物学方法,以鉴定与高淀粉样变性引起的AD的大脑易损性有关的新因素。我们首先检查了散发性AD患者的神经退行性特异性基因特征以及年轻的转基因AD小鼠的突触蛋白变化。然后,我们系统地评估了顶级候选基因与AD的关联,并研究了其在神经退行性变中的机制作用。结果我们确定了卵巢定向蛋白OCIAD1(卵巢癌-免疫反应-抗原-域-包含1)是AD的神经退行性相关因素。在脆弱的大脑区域和营养不良的神经突中发现的较高水平的OCIAD1与疾病严重程度相关。多个早期AD病理事件,尤其是Aβ/GSK-3β信号,升高了OCIAD1,OCIAD1反过来又与BCL-2相互作用,损害线粒体功能并促进线粒体相关的神经元损伤。值得注意的是,通过Aβ升高的OCIAD1可以增加细胞对其他AD病理学挑战的敏感性。解释我们的发现表明,OCIAD1通过损害线粒体功能,进而导致神经元脆弱性和突触损伤,促进了AD的神经变性。筹款Tsung Tsung和Wei Fong Chao基金会,John S Dunn研究基金会,Cure Alzheimer基金会和STCW的NIH R01AG057635。