Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Xu, Xiaoyan; Sun, Yaqin; Cen, Xufeng; Shan, Bing; Zhao, Qiu; Xie, Tingxue; Wang, Zhe; Hou, Tingjun; Xue, Yu; Zhang, Mengmeng; Peng, Di; Sun, Qiming; Yi, Cong; Najafov, Ayaz; Xia, Hongguang

doi:10.1007/s13238-021-00858-3

Cited by 81 publications

(69 citation statements)

References 66 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides, chaperone-mediated autophagy (CMA), a lysosome-dependent selective degradation pathway, was also implicated in DNA methylation ( Dice, 2007 ). CMA was reported to be suppressed at an early stage of AD and its activation could reduce the levels of Aβ plaques and tau phosphorylation, and ameliorate behavioral phenotype ( Dou et al, 2020 ; Bourdenx et al, 2021 ; Xu X. et al, 2021 ; Caballero et al, 2021 ). These evidences support an unequivocal role for CMA in the development of AD.…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis

Song

Yang

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is characterized by the abnormal deposition of amyloid-β (Aβ) plaques and tau tangles in the brain and accompanied with cognitive impairment. However, the fundamental cause of this disease remains elusive. To elucidate the molecular processes related to AD, we carried out an integrated analysis utilizing gene expression microarrays (GSE36980 and GSE5281) and DNA methylation microarray (GSE66351) in temporal cortex of AD patients from the Gene Expression Omnibus (GEO) database. We totally discovered 409 aberrantly methylated and differentially expressed genes. These dysregulated genes were significantly enriched in biological processes including cell part morphogenesis, chemical synaptic transmission and regulation of Aβ formation. Through convergent functional genomic (CFG) analysis, expression cross-validation and clinicopathological correlation analysis, higher TGFBR3 level was observed in AD and positively correlated with Aβ accumulation. Meanwhile, the promoter methylation level of TGFBR3 was reduced in AD and negatively associated with Aβ level and advanced Braak stage. Mechanically, TGFBR3 might promote Aβ production by enhancing β- and γ-secretase activities. Further investigation revealed that TGFBR3 may exert its functions via Synaptic vesicle cycle, Calcium signaling pathway and MAPK signal pathway by regulating hub genes GNB1, GNG3, CDC5L, DYNC1H1 and FBXW7. Overall, our findings highlighted TGFBR3 as an AD risk gene and might be used as a diagnostic biomarker and therapeutic target for AD treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis

Song

Yang

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Is it the structure of the receptor that determines this process and is there a propensity to degrade the damaged protein under certain conditions? In one recent study, APP protein was found to be the receptor of CMA [ 240 ], and APP could conduct both macroautophagy and CMA. However, how to conduct macroautophagy and CMA, and whether there is a priority between the two are problems to be solved in the future.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights into Selective Autophagy Subtypes in Alzheimer’s Disease

Guan

Iyaswamy

Sreenivasmurthy

et al. 2022

IJMS

View full text Add to dashboard Cite

Eukaryotic cells possess a plethora of regulatory mechanisms to maintain homeostasis and ensure proper biochemical functionality. Autophagy, a central, conserved self-consuming process of the cell, ensures the timely degradation of damaged cellular components. Several studies have demonstrated the important roles of autophagy activation in mitigating neurodegenerative diseases, especially Alzheimer’s disease (AD). However, surprisingly, activation of macroautophagy has not shown clinical efficacy. Hence, alternative strategies are urgently needed for AD therapy. In recent years, selective autophagy has been reported to be involved in AD pathology, and different subtypes have been identified, such as aggrephagy, mitophagy, reticulophagy, lipophagy, pexophagy, nucleophagy, lysophagy and ribophagy. By clarifying the underlying mechanisms governing these various subtypes, we may come to understand how to control autophagy to treat AD. In this review, we summarize the latest findings concerning the role of selective autophagy in the pathogenesis of AD. The evidence overwhelmingly suggests that selective autophagy is an active mechanism in AD pathology, and that regulating selective autophagy would be an effective strategy for controlling this pathogenesis.

show abstract

“…Conversely, LAMP2A overexpression attenuates neurodegeneration in cellular and animal models of Parkinson’s disease [ 46 ]. Moreover, the chemicals that activate CMA have therapeutic effects in cellular and animal models of Alzheimer’s disease [ 44 , 47 ]. These findings suggest that CMA can be a potential target for the treatment of various neurodegenerative diseases, including SCA, Parkinson’s disease, and Alzheimer’s disease.…”

Section: Discussionmentioning

confidence: 99%

D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Ueda

Ohta

Konno

et al. 2022

Cells

View full text Add to dashboard Cite

Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation.

show abstract

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

Cited by 81 publications

References 66 publications

Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis

Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis

Mechanistic Insights into Selective Autophagy Subtypes in Alzheimer’s Disease

D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Contact Info

Product

Resources

About