The Role of Beclin-1 Acetylation on Autophagic Flux in Alzheimer’s Disease

Esteves, A. Raquel; Filipe, Filipa; Magalhães, João Duarte; Silva, Diana F.; Cardoso, Sandra M.

doi:10.1007/s12035-019-1483-8

Cited by 33 publications

(27 citation statements)

References 72 publications

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“… 108 Starvation does not prolong longevity if mTOR signalling is already suppressed, 128 and conversely, mTOR inhibition with rapamycin does not favourably affect survival if autophagy genes are already knocked down or out. 136 Conversely, SIRT1 deacetylases (and thereby activates) several autophagy genes 137 ; SIRT1-mediated deacetylation of beclin 1 promotes autophagic flux 138 ; and PGC-1α interacts with the E3 ubiquitin ligase Parkin to mediate mitophagy. 139 , 140 Importantly, the longevity effects of SIRT1 are mediated by its actions to promote autophagy, 141 and caloric restriction does not induce mitochondrial autophagy in aged animals if SIRT1 is absent.…”

Section: Mechanisms Underlying the Effects Of Sirt1 Ampk And Akt/mtmentioning

confidence: 99%

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Packer

2020

European Heart Journal

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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Section: Mechanisms Underlying the Effects Of Sirt1 Ampk And Akt/mtmentioning

confidence: 99%

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Packer

2020

European Heart Journal

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“…Beclin 1, a protein with a key role in autophagy, decreases in brain regions of patients with AD (Pickford et al, 2008). Either heterozygous deletion or mutation of Beclin 1 in mice decreases neuronal autophagy and results in neurodegeneration and disruption of lysosomes (Esteves et al, 2019; Lee & Gao, 2008; Pickford et al, 2008; La Spada et al, 2017). Activation of autophagy decreases Aβ pathology and alleviates cognitive dysfunction in various animal models (Steele et al, 2013; Yang et al, 2011a, 2011b; Yi et al, 2020; Yu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Wang

Liu

et al. 2021

Aging Cell

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Alzheimer's disease (AD) is an age‐related neurodegenerative disease, and the imbalance between production and clearance of β‐amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up‐regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up‐regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ‐induced injury. The neuroprotection by thioperamide against AD was reversed by 3‐MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic‐related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic‐lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB‐dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB‐mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

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“…Recent studies have shown that Beclin 1 can be acetylated by p300 acetyltransferase, and acetylated Beclin 1 promotes the recruitment of Rubicon and inhibits autophagosome maturation and endocytic trafficking 43 , 44 . To verify this, we examined the effect of amitriptyline on the acetylation of Beclin 1.…”

Section: Resultsmentioning

confidence: 99%

Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

et al. 2020

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Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.

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The Role of Beclin-1 Acetylation on Autophagic Flux in Alzheimer’s Disease

Cited by 33 publications

References 72 publications

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

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