Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy–lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy–lysosomal pathway in AD. We then describe the interplay between the autophagy–lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy–lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy–lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy–lysosomal pathway for AD treatment.     

脾气虚大鼠胃黏膜细胞线粒体自噬相关蛋白表达的研究＊

目的 通过检测PTEN诱导激酶1（PTEN-induced putative kinase protein 1，PINK1）-Parkin通路及自噬相关蛋白表达，探讨脾气虚胃黏膜细胞线粒体损伤的可能机制。方法 16只雄性SD大鼠随机分为正常组和脾气虚证模型组（模型组），每组8只；透射电镜观察胃黏膜细胞线粒体形态，JC-1法测量其膜电位（ΔΨm）；比色法测定其ATP含量和呼吸链复合物（respiratory chain complex，RCC）I-IV活性；Western blot法检测其RCCV、PINK1、Parkin、微管相关蛋白1轻链3（microtubule-associated protein light chain 3，LC3）-I和II及p62等表达。结果 与正常组比较，模型组胃黏膜细胞的线粒体嵴减少，ΔΨm和ATP水平下降，RCCI和IV活性降低，RCCV、PINK1、Parkin和LC3-II表达下降，但LC3-I和p62表达上升。结论 脾气虚胃黏膜细胞线粒体结构和功能损伤与PINK1-Parkin通路抑制所导致的线粒体自噬水平低下有关。     

Repeated radon exposure induced lung damage via oxidative stress-mediated mitophagy in human bronchial epithelial cells and mice

This study aimed to investigate the potential molecular mechanism underlying radon-induced lung damage. Our results showed that long-term radon exposure induced mitochondrial damage and redox imbalance in BEAS-2B cells and a time-dependent lung pathological injury in mice. The activation of Nrf-2 and its down-stream antioxidants, and the gene expression of the indicated markers at different stages of autophagy were found to be induced with the increasing of radon exposure time. Changes in the gene expression of PINK-1, Parkin, and p62 induced by radon showed differences in mechanisms of mitophagy activation and profiles of autophagic flux between BEAS-2B cells and mice. Our findings not only demonstrated that long-term radon exposure induced damages to bronchial epithelial cells and the mice lung through increasing oxidative stress, decreasing mitochondrial function and activating mitophagy with different profiles of autophagic flux, but also revealed Nrf-2 as a central regulator of mitochondrial homeostasis and lung damage.