DNA 损伤相关的少突胶质细胞退化先于淀粉样蛋白病理，并导致阿尔茨海默病和痴呆。
DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia.
机构信息
Division of Life Science & State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Division of Life Science & State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
出版信息
Alzheimers Dement. 2018 May;14(5):664-679. doi: 10.1016/j.jalz.2017.11.010. Epub 2018 Jan 9.
INTRODUCTION
In looking for novel non-amyloid-based etiologies for Alzheimer's disease, we explore the hypothesis that age-related myelin loss is an attractive explanation for age-associated cognitive decline and dementia.
METHODS
We performed a meta-analysis of data in the National Alzheimer's Coordinating Center database accompanied by quantitative histopathology of myelin and oligodendrocytes (OLs) in frontal cortices of 24 clinically characterized individuals. Pathological findings were further validated in an Alzheimer's disease mouse model and in culture.
RESULTS
Myelin lesions increased with cognitive impairment in an amyloid-independent fashion with signs of degeneration appearing before neuronal loss. Myelinating OLs in the gray matter showed greater vulnerability than those in white matter, and the degenerative changes correlated with evidence of DNA damage. Similar results were found in myelinating OL cultures where DNA damage caused aberrant OL cell cycle re-entry and death.
DISCUSSION
We present the first comprehensive analysis of the cell biology of early myelin loss in sporadic Alzheimer's disease.
简介
在寻找阿尔茨海默病新的非淀粉样蛋白病因时，我们探讨了这样一个假设，即与年龄相关的髓鞘丢失是解释与年龄相关的认知能力下降和痴呆的一个有吸引力的原因。
方法
我们对国家阿尔茨海默病协调中心数据库中的数据进行了荟萃分析，并对 24 名临床特征明确的个体的额皮质中的髓鞘和少突胶质细胞 (OLs) 进行了定量组织病理学检查。在阿尔茨海默病小鼠模型和培养物中进一步验证了病理发现。
结果
髓鞘病变与认知障碍呈非淀粉样蛋白依赖方式相关，且在神经元丢失之前出现退行性改变的迹象。灰质中的髓鞘形成 OL 比白质中的更脆弱，退行性变化与 DNA 损伤的证据相关。在髓鞘形成 OL 培养物中也发现了类似的结果，其中 DNA 损伤导致 OL 细胞周期异常重新进入和死亡。
讨论
我们首次全面分析了散发性阿尔茨海默病中早期髓鞘丢失的细胞生物学。
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