Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications

Chen, Jie; He, Hai-Jun; Ye, Qianqian; Feng, Feifei; Wang, Wenwen; Gu, Yingying; Han, Ruiyu; Xie, Chenglong

doi:10.1007/s12035-021-02487-7

Cited by 23 publications

(6 citation statements)

References 110 publications

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“…The brains of patients with AD show impaired glucose and oxygen metabolism and impaired activity of pyruvate dehydrogenase, ketoglutarate dehydrogenase, and cytochrome oxidase. Furthermore, mtDNA alterations, dysfunctional transmembrane amyloid beta, and tau protein accumulation are found, together with altered mitochondria morphology and respiratory chain dysfunction ( Chen et al, 2021a ; Castora et al, 2022 ; Rey et al, 2022 ).…”

Section: Part Ii: Mitochondrial Dysfunction and Its Involvement In Di...mentioning

confidence: 99%

Mitochondria: It is all about energy

et al. 2023

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Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.

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Section: Part Ii: Mitochondrial Dysfunction and Its Involvement In Di...mentioning

confidence: 99%

Mitochondria: It is all about energy

et al. 2023

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“…Regretfully, most efforts in developing effective immunotherapy against AD did not produce effective results and also the use of aducanumab is still debated and its actual efficacy has not been completely proved (Whitehouse et al, 2022 ). The increasing characterization of the mechanisms of proteostasis and the evidence of a relationship between UPS and ALP malfunctioning and accumulation of misfolded proteins is opening a new therapeutic strategy focused on restoring protein metabolism control in neurons, rather than acting on the disease-specific proteins, might pave the way for future therapeutic approaches possibly acting on all proteopathies (Gregori et al, 1995 ; Ciechanover and Brundin, 2003 ; Ciechanover and Kwon, 2017 ; Thellung et al, 2019 ; Chen et al, 2021 ; Leri et al, 2021 ).…”

Section: The Present and The Future Of Neuroprotective Therapies Targ...mentioning

confidence: 99%

Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets

et al. 2022

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Transmissible spongiform encephalopathies (TSEs), or prion diseases, are progressive neurodegenerative disorders of the central nervous system that affect humans and animals as sporadic, inherited, and infectious forms. Similarly to Alzheimer's disease and other neurodegenerative disorders, any attempt to reduce TSEs' lethality or increase the life expectancy of affected individuals has been unsuccessful. Typically, the onset of symptoms anticipates the fatal outcome of less than 1 year, although it is believed to be the consequence of a decades-long process of neuronal death. The duration of the symptoms-free period represents by itself a major obstacle to carry out effective neuroprotective therapies. Prions, the infectious entities of TSEs, are composed of a protease-resistant protein named prion protein scrapie (PrPSc) from the prototypical TSE form that afflicts ovines. PrPSc misfolding from its physiological counterpart, cellular prion protein (PrPC), is the unifying pathogenic trait of all TSEs. PrPSc is resistant to intracellular turnover and undergoes amyloid-like fibrillation passing through the formation of soluble dimers and oligomers, which are likely the effective neurotoxic entities. The failure of PrPSc removal is a key pathogenic event that defines TSEs as proteopathies, likewise other neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, characterized by alteration of proteostasis. Under physiological conditions, protein quality control, led by the ubiquitin-proteasome system, and macroautophagy clears cytoplasm from improperly folded, redundant, or aggregation-prone proteins. There is evidence that both of these crucial homeostatic pathways are impaired during the development of TSEs, although it is still unclear whether proteostasis alteration facilitates prion protein misfolding or, rather, PrPSc protease resistance hampers cytoplasmic protein quality control. This review is aimed to critically analyze the most recent advancements in the cause-effect correlation between PrPC misfolding and proteostasis alterations and to discuss the possibility that pharmacological restoring of ubiquitin-proteasomal competence and stimulation of autophagy could reduce the intracellular burden of PrPSc and ameliorate the severity of prion-associated neurodegeneration.

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“…Increasing studies suggest that Ca 2+ dysregulation in AD plays an important role in AD pathology and is associated with other AD abnormalities, such as excessive inflammation, increased ROS, impaired autophagy, neurodegeneration, and synapse and cognitive dysfunction [ 2 , 3 , 4 , 5 ]. Autophagy is important for removing unnecessary or dysfunctional components and long-lived protein aggregates, and a substantial amount of evidence in both AD patients and AD animal models indicates autophagy dysregulation plays an important role in AD pathogenesis [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Autophagy can also be regulated by intracellular Ca 2+ signals arising from different organelles, including ER, mitochondria and lysosomes [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease

Zhang

Bezprozvanny

2023

Life

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Alzheimer’s disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium (Ca2+) signaling plays a major role in the initiation of AD pathogenesis. In particular, it is well established that Ryanodine receptor (RyanR) expression levels are increased in AD neurons and Ca2+ release via RyanRs is augmented in AD neurons. Autophagy is important for removing unnecessary or dysfunctional components and long-lived protein aggregates, and autophagy impairment in AD neurons has been extensively reported. In this review we discuss recent results that suggest a causal link between intracellular Ca2+ signaling and lysosomal/autophagic dysregulation. These new results offer novel mechanistic insight into AD pathogenesis and may potentially lead to identification of novel therapeutic targets for treating AD and possibly other neurodegenerative disorders.

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Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications

Cited by 23 publications

References 110 publications

Mitochondria: It is all about energy

Mitochondria: It is all about energy

Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets

“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease

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