Enhancement of oligodendrocyte autophagy alleviates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion in rats

Cognitive impairment caused by chronic cerebral hypoperfusion (CCH) is associated with white matter injury (WMI), possibly through the alteration of autophagy. Here, the autophagy-lysosomal pathway (ALP) dysfunction in white matter (WM) and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion (2VO). The results showed that cognitive impairment occurred by the 28th day after 2VO. Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day. By the 14th day, abnormal accumulation of autophagy substrate, lysosomal dysfunction, and the activation of mechanistic target of rapamycin (MTOR) pathway were observed in WM, paralleled with mature oligodendrocyte death. This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction. To target the ALP dysfunction, enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1 (BECN1) in oligodendrocytes reduced mature oligodendrocyte death, and subsequently alleviated the WMI and cognitive impairment after CCH. These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO, which was associated with the aggravation of WMI and cognitive impairment. This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.

Empagliflozin ameliorates renal tissue damage in diabetic nephropathy mice through autophagy-lysosome pathway / 中国药理学通报

Aim To investigate the effeots of empagliflozin on kidney tissue and autophagy-lysosome pathway in diabetio kidney disease (DKD) mice. Methods The db/m group as the control group, the db/db mice were randomly divided into the model group and empagliflozin group. After 8 weeks of administration, the levels of 24 h urine protein (24 h-UTP), fasting blood glucose (FBG), glycosylated hemoglobin (HBAlc), total cholestérol (TC), triglycéride (TG), blood urea nitrogen (BUN), serum creatinine (Scr), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β, and monocyte chemoattractant protein-1 (MCP-1) were detected. The expression of p62, LC3B, Beclinl, Agt7, LAMP1, Bcl-2, caspase-3 and Bax in kidney tissue was measured by Western blot. The pathological changes of kidney were observed under light microscope. Results Compared with the control group, the model group showed thickening of basement membrane, increased extracellular matrix, interstitial inflammatory cell infiltration and interstitial fibrosis (P < 0. 01). Moreover, the model group had higher content of FBG, HBAlc, 24h-UTP, TC, TG, BUN, Scr, TNF-α, IL-1β, and MCP-1 (P < 0. 01), higher expression of LC3B-/LC3B- I, Beclinl, LAMP1, Agt7 and Bcl-2 (P<0. 01), and lower expression of p62, caspase-3 and Bax in rénal tissue (P < 0. 01) than those in the control group. Compared with the model group, empagliflozin alleviated the pathological injury in kidney (P < 0. 01), and the changes in the above indicators were reversed. Conclusion By irepairing autophagy-lysosomal pathway in renal tissue, empagliflozin can promote the degradation of autophagy substrates, inhibit the production of inflammatory factors and apoptosis, thereby protecting the kidney.

Research Progress on Mechanism of Acupuncture for Neurological and Other Diseases by Regulating Autophagy-Lysosomal Pathway / 中山大学学报(医学科学版)

As an important part of traditional Chinese medicine， the efficacy and scientificity of acupuncture have attracted more and more attention. In recent years， rigorous randomized controlled clinical trials have confirmed the efficacy of acupuncture on certain dominant diseases， and basic researches have partially revealed the mechanism of acupuncture for treating diseases. By analyzing published literatures and referring to relevant studies from our research team， this paper reviews the mechanisms of acupuncture for treating neurological and other diseases via regulating the autophagy-lysosomal pathway （ALP）. We found that acupuncture improved related pathologies in different disease models by up-regulating or down-regulating ALP， and there is a certain correlation between the distribution of acupoints and the one-way/two-way regulation of ALP； however， the current studies have some defects in experimental design and methodology， and the molecular mechanisms of acupuncture on ALP regulation remain to be further elucidated.

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.

Effects of an autophagy/lysosomal pathway induced by 6-hydroxydopamine in PC12 cells / 中华行为医学与脑科学杂志

Objective To investigated the role of the autophagy lysosomal pathway in PD cells and the possible molecular mechanisms. Methods A dopaminergic neuronal injury model was induced by 6-OHDA in PC12 cells . Autophagosomes in PC12 cells were examined by transmission electronmicro-scopy( TEM ). The expression of LC3- Ⅱ , Cathepsin B were assayed by western blot analysis. Results TEM revealed that the autophagosomes were increased in PC12 cells after 6-OHDA treatment and appeared apoptosis. The LC3-Ⅱ (2h:52.57 ±2.27,4h:56.83 ±3.51,6h:73.43 ±5.41,12h:103.90 ±2.57,24h: 100.40 ±3.91 )and Cathepsin B expression ( model group: 113.80 ± 4.46; normal group 35.89 ± 3.40) were increased after 6-OH DA treatments (P ＜ 0.05 or P ＜ 0.01 ). Conclusion The results indicate that autophagy lysosome pathway is involved in 6-OHDA-induced cell death in PC12 cells.