SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Lee, Jung‐Hee; Kim, Yunha; Liu, Tian; Hwang, Yu Jin; Hyeon, Seung Jae; Im, Hyeonjoo; Lee, Kyung‐Eun; Alvarez, Victor E.; McKee, Ann C.; Um, Soo‐Jong; Hur, Man‐Wook; Mook‐Jung, Inhee; Kowall, Neil W.; Ryu, Hoon

doi:10.1111/acel.12679

Cited by 163 publications

(125 citation statements)

References 56 publications

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“…Most recently, overexpression of SIRT3 was demonstrated to prevent αsyn-induced neurodegeneration in a rodent AAV model (Gleave et al, 2017). In humans, down downregulation of SIRT3 has been previously reported in post-mortem human Alzheimer disease brain (Han et al, 2014; Lee et al, 2018).…”

Section: Discussionmentioning

confidence: 86%

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Park

Delenclos

Faroqi

et al. 2018

Preprint

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20The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD + )-dependent en-21 zymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 22 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neuro-23 degeneration and plays a major role in maintaining mitochondrial function and preventing 24 oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease 25 with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing famil-26 ial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein (αsyn) oli-27 gomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and 28 decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of 29 αsyn accumulation is accompanied by increased phosphorylation of AMP-activated protein 30 kinase (AMPK) and cAMP-response element binding protein (CREB), as well as increased 31 phosphorylation of dynamin-related protein 1 (DRP1) and decreased levels of optic atrophy 1 32 (OPA1), which is indicative of impaired mitochondrial dynamics. Treatment with the AMPK 33 agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 ex-34 pression and activity and improves mitochondrial function by decreasing αsyn oligomer for-35 mation. The accumulation of αsyn oligomers in mitochondria corresponds with SIRT3 down-36 regulation not only in an experimental cellular model, but also in vivo in a rodent model of 37 Parkinson disease, and importantly, in human post mortem brains with neuropathologically 38 confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacolog-39 ically increasing SIRT3 levels will counteract αsyn-induced mitochondrial dysfunction by 40 normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in 41 Parkinson disease-associated pathways and reveals significant mechanistic insight into the 42 interplay of SIRT3 and αsyn. 43 44 45 46 Abbreviations: SIRT3, Sirtuin 3; α-synuclein; αsyn; AMPK, adenosine monophosphate acti-47 vated protein kinase; CREB, cAMP-response element binding protein; DRP1, dynamin-48 related protein 1; OPA1, optic atrophy 1; HO-1, heme oxygenase-1; SOD2, superoxide dis-49 mutase 2; mtROS, mitochondrial reactive oxygen species. 50 51Alpha-synuclein (αsyn) accumulation is believed to be a key step in the pathogenesis of Par-53 kinson's disease and related alpha-synucleinopathies. Despite predominant localization in the 54 cytosol, αsyn is found localized to mitochondria in post-mortem Parkinson's disease brain 55 (Devi et al., 2008). Mitochondrial accumulation of αsyn has been associated with impairment 56 of complex-I dependent respiration, decreased mitochondria membrane potential, and in-57 creased levels of mitochondrial reactive oxygen species (mtROS) in multiple cellular models 58 (Hsu et al., 2000; Devi et al., 2008; Reeve et al., 2015; Ludtmann et al., 2018). The evidence 59 suppo...

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Section: Discussionmentioning

confidence: 86%

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Park

Delenclos

Faroqi

et al. 2018

Preprint

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“…[ 22 ] Previous study indicated that SIRT3 activation could lower Aβ and Tau accumulation in the brain of AD mice, playing a neuroprotective role in reducing oxidative neurotoxicity. [ 23,24 ] Activation of SIRT3 could mediate hippocampal synaptic adaptations and ameliorate cognitive deficits in APP mutant mice. [ 25 ] Moreover, SIRT3 deficiency could induce brain mitochondrial dysfunction, microgliosis and elevate NLRP3 inflammasomes and IL‐1β expression, which exacerbated cognitive decline in calorie‐rich western diet induced mice.…”

Section: Discussionmentioning

confidence: 99%

5‐Heptadecylresorcinol, a Biomarker for Whole Grain Rye Consumption, Ameliorates Cognitive Impairments and Neuroinflammation in APP/PS1 Transgenic Mice

Liu

Wang

et al. 2020

Molecular Nutrition Food Res

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Scope 5‐heptadecylresorcinol (AR‐C17) is a biomarker for whole grain rye consumption, which is also an important active component with potential health benefits. The aim of this study is to investigate the protective effect of AR‐C17 on cognitive deficits in amyloid precursor protein (APP)/PS1 transgenic mice. Methods and results Cognitive function is evaluated using Morris water maze test. The result shows that oral administration of AR‐C17 (150 mg kg−1 day−1) for 5 months can ameliorate APP/PS1 transgenic mice memory impairment and improve learning ability. Moreover, AR‐C17 treatment can notably reduce β‐amyloid plaques accumulation and tau hyperphosphorylation while enhancing a disintegrin and metalloprotease 10 (ADAM10), postsynaptic density protein‐95 (PSD‐95), and synaptophysin protein expression in APP/PS1 transgenic mice. Furthermore, AR‐C17 treatment reduces neuroinflammation by inhibiting microglial activation and astrogliosis as well as decreasing NOD‐like receptor family, pyrin domain‐containing 3 (NLRP3) inflammasome‐mediated IL‐1β production and activating the sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) signaling pathway. Additionally, AR‐C17 consumption significantly modulated gut dysbiosis in APP/PS1 transgenic mice through improving the relative abundance of Akkermansia and Lactobacillus while reducing the abundance of Clostridium and Desulfovibr according to16S rRNA analysis. Conclusion AR‐C17 can be applied as a potential functional food ingredient to ameliorate cognitive impairments and prevent Alzheimer's disease.

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“…As well known, in physiological condition deacetylated p53 prevents DNA damage and mitochondrial dysfunctions, but Alzheimer's patients exhibit a decrease of Sirt3 which is associated to an accumulation of acetylated p53 in the mitochondria of frontal cortex neurons. In this context, the direct deacetylation of mitochondrial p53 on lysine 320 by Sirt3 had neuroprotective effect on Alzheimer's disease slowing its progression [103].…”

Section: Sirtuins In Neurodegenerative Disorders Of Interest For Rehamentioning

confidence: 99%

Controversial Impact of Sirtuins in Chronic Non-Transmissible Diseases and Rehabilitation Medicine

Mongelli¹,

Gaetano²

2018

Preprint

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A large body of evidence report about the positive effects of physical activity in some pathophysiological conditions associated with age. Physical exercise alone or in combination with other medical therapies, unquestionably, causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting therapeutic outcome, however, remain obscure. Epigenetics, exploring at the interface between the environment and the remodelling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of class III histone deacetylases (HDACs), sirtuins (Sirts), which altered function has been frequently associated to the pathogenesis of aging-associated diseases including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases, often with a controversial role. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking the modulation of mitochondrial function, DNA structure and gene expression to designed medical therapies eventually leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. Nevertheless, to study sirtuins in chronic diseases might lead to improve life quality in the elderly.

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SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Cited by 163 publications

References 56 publications

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

5‐Heptadecylresorcinol, a Biomarker for Whole Grain Rye Consumption, Ameliorates Cognitive Impairments and Neuroinflammation in APP/PS1 Transgenic Mice

Controversial Impact of Sirtuins in Chronic Non-Transmissible Diseases and Rehabilitation Medicine

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