Abstract:
Alzheimer\'s disease (AD) is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. By far, the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease. Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles, pathogens, and disease-prone protein aggregates to lysosome for degradation. Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons. Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells. Finally, we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.
摘要:
阿尔茨海默病(AD)是一种普遍存在的有害神经退行性疾病,其特征是认知能力的不可逆和进行性损害以及脑中淀粉样蛋白β(Aβ)斑块和神经原纤维缠结(NFT)的形成。到目前为止,AD的确切机制尚不完全清楚,目前尚无有效减缓疾病进展的干预措施.自噬是一种保守的降解途径,通过靶向受损的细胞器来维持细胞内稳态至关重要。病原体,和疾病倾向的蛋白质聚集到溶酶体降解。新的证据表明,功能失调的自噬清除途径是受影响的神经元中AD发病机理的潜在细胞机制。在此,我们总结了目前在AD病理生理学中自噬功能障碍的证据,并讨论了自噬在调节AD相关蛋白降解和神经元和神经胶质细胞神经炎症中的作用。最后,我们回顾了在AD模型治疗中报道的自噬调节剂,并讨论了新型自噬激活剂用于AD治疗的潜在临床应用的障碍和机会。