The Mechanism of Autophagy Regulation and The Role of Autophagy in Alzheimer′s Disease
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Autophagy is a main pathway that clears the dysfunction organelles,misfolding proteins and oxidative lipids.It's important for maintaining life activity and conserved from yeast to mammalian.In the AD neurons the misfolding proteins were not efficiently cleared then accumulated.These caused neurons loss of function even neuron death.This review focuses on the recent progresses on regulation of autophagy and the role of autophagy in Alzheimer's diseases.Autophagy is protective in early stage of AD,although it induces autophagic cell death in late stage of AD.Autophagosome may be the main site for Aβ production and clearance.Presenilin 1 which is the key proteinase in γ-secrectase also plays a role in lysosomal acidification which is a key step for autophagic degradation.Tau may be involved in autophagosome trafficking and autophagosome-lysosome fusion.mTOR and AMPK sensing nutrients and energy in cells also regulate autophagy.Keywords:
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Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.
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Autophagy is a stress response that is upregulated in response to signals such as starvation, growth factor deprivation, endoplasmic reticulum stress, and pathogen infection. Defects in this pathway are the underlying cause of a number of diseases, including metabolic aberrations, infectious diseases, and cancer, which are closely related to hepatic disorders. To date, more than 30 human ATG (autophagy) genes have been reported to regulate autophagosome formation. In this review, we summarize the current understanding of how ATG proteins behave during autophagosome formation in both non‐selective and selective autophagy.
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The autophagy-lysosomal pathway is a major proteolytic pathway that in mammalian systems mainly comprises of macroautophagy and chaperone-mediated autophagy. The former is relatively non-selective and involves bulk degradation of proteins and organelles, whereas the latter is selective for certain cytosolic proteins. These autophagy pathways are important in development, differentiation, cellular remodeling and survival during nutrient starvation. Autophagy is crucial for neuronal homeostasis and acts as a local housekeeping process, since neurons are post-mitotic cells and require effective protein degradation to prevent accumulation of toxic aggregates. A growing body of evidence now suggests that dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles. Such accumulation has been linked to synaptic dysfunction, cellular stress and neuronal death. Abnormal autophagy may be involved in the pathology of both chronic nervous system disorders, such as proteinopathies (Alzheimers, Parkinsons, Huntingtons disease) and acute brain injuries. Although autophagy is generally beneficial, its aberrant activation may also exert a detrimental role in neurological diseases depending on the environment and the insult, leading to autophagic neuronal death. In this review we summarize the current knowledge regarding the role of autophagy-lysosomal pathway in the central nervous system and discuss the implication of autophagy dysregulation in human neurological diseases and animal models. Keywords: Autophagosome, chaperone-mediated autophagy, LAMP-2A receptor, LC3, macroautophagy, neurodegenerative diseases, autophagy-lysosomal pathway, Parkinson's disease, Lewy body dementias, Alzheimer's disease, Huntington's disease, Prion Diseases, Frontotemporal dementias, Amyotrophic lateral sclerosis, microautophagy, pexophagy, reticulophagy, ER-phagy, rapamycin, mTOR, autophagolysosomes, amphisomes, Atg14L, Rubicon, UVRAG, MAP1LC3, ESCRT, LAMP-2A, HDAC6, Ambra1, CHMP4B, neuronal ceroid lipofuscinosis, Batten disease, C elegans, metamphetamine-induced injury, KFERQ, ASYN gene, MEF2D, Bafilomycin, SMER, amyloidogenesis, polyQ diseseases, spinobulbar muscular atrophy, dentatorubral, pallidoluysian atrophy, temsirolimus, Scrg1, Creutzfeldt-Jakob disease, NIEMANN-PICK C DISEASE
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// Martyna Bednarczyk 1 , Nikola Zmarzły 2 , Beniamin Grabarek 2 , Urszula Mazurek 2 and Małgorzata Muc-Wierzgoń 1 1 Department of Internal Diseases, School of Public Health in Bytom, Medical University of Silesia in Katowice, 40–055 Katowice, Poland 2 Department of Molecular Biology, School of Pharmacy with The Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, 40–055 Katowice, Poland Correspondence to: Martyna Bednarczyk, email: martyna.bednarczyk@outlook.com Keywords: autophagy; lysosome; chaperones; mitochondria; cancer Received: March 15, 2018 Accepted: August 30, 2018 Published: September 28, 2018 ABSTRACT Autophagy is a highly conserved mechanism of self-digestion that removes damaged organelles and proteins from cells. Depending on the way the protein is delivered to the lysosome, four basic types of autophagy can be distinguished: macroautophagy, selective autophagy, chaperone-mediated autophagy and microautophagy. Macroautophagy involves formation of autophagosomes and is controlled by specific autophagy-related genes. The steps in macroautophagy are initiation, phagophore elongation, autophagosome maturation, autophagosome fusion with the lysosome, and proteolytic degradation of the contents. Selective autophagy is macroautophagy of a specific cellular component. This work focuses on mitophagy (selective autophagy of abnormal and damaged mitochondria), in which the main participating protein is PINK1 (phosphatase and tensin homolog-induced putative kinase 1). In chaperone-mediated autophagy, the substrate is bound to a heat shock protein 70 chaperone before it is delivered to the lysosome. The least characterized type of autophagy is microautophagy, which is the degradation of very small molecules without participation of an autophagosome. Autophagy can promote or inhibit tumor development, depending on the severity of the disease, the type of cancer, and the age of the patient. This paper describes the molecular basis of the different types of autophagy and their importance in cancer pathogenesis.
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自噬为真核细胞独有的代谢过程，基础自噬通过清除衰老的细胞器和异常堆积的蛋白，保证其正常的细胞功能。然而失调的自噬或者过多的自噬都会导致细胞死亡。在AD患者或转基因AD鼠的神经细胞中存在大量的自噬囊泡，表明自噬可能参与了阿尔茨海默病的发生、发展。因此，明确自噬在AD 发病不同阶段的确切作用可能有助于发现更为有效的治疗靶点。 Autophagy is a unique metabolic process for eukaryotic cells, and basal autophagy protects its normal cellular function by removing damaged organelles and abnormally aggregated proteins. However, abnormal autophagy or excessive autophagy can lead to cell death. There are a large number of autophagic vesicles in the nerve cells of Alzheimer’s patients or transgenic mice, sug-gesting that autophagy may be involved in the development and progression of Alzheimer’s disease. Thus, the exact role of autophagy at different stages of AD pathogenesis may help to find more effective therapeutic targets.
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Abstract Background Autophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer’s Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined. Methods Here, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (Aβ42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls’ test. Results Aβ42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1β, TNF-α, and IL-6) or IL-1β alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1β in the induction of autophagy in tri-cultures in the presence or absence of Aβ42. However, the vulnerability of the autophagic process in purified microglia to IL-1β was prevented by Aβ42. Conclusion These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1β in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.
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Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.
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Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.
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