RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

Wang, Yan; Yang, Jingqi; Hong, Tang; Sun, Yuanhong; Huang, Haili; Chen, Feng; Chen, Xiongjin; Chen, Huiyi; Dong, Shanshan; Cui, Lili; Yang, Tie‐Lin

doi:10.1111/acel.13194

Cited by 43 publications

(52 citation statements)

References 36 publications

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“…Moreover, the compound AK-1, a SIRT2 inhibitor, which was administered directly into the hippocampus, protected from neurodegeneration in a Tau transgenic mouse model without affecting neurofibrillary tangles [ 77 ]. In addition, other groups showed that SIRT2 inhibition improved cognitive performance in different AD transgenic mouse models via APP amyloidogenic processing [ 78 , 79 ] and Tau and microtubule stability modulation [ 78 ]. Accordingly, its inhibition or knock-out also improved autophagy and decreased typical AD cytoskeletal pathology [ 29 ], decreased Tau phosphorylation, and increased Tau/tubulin binding, improving microtubule dynamics [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

Sola-Sevilla

Ricobaraza

Hernández-Alcoceba

et al. 2021

IJMS

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Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1β. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.

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Section: Resultsmentioning

confidence: 99%

Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

Sola-Sevilla

Ricobaraza

Hernández-Alcoceba

et al. 2021

IJMS

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“…The ADAM10 activation also leads to the Notch receptor cleavage, which targets the genes that are vital for memory learning and synaptic plasticity ( Costa et al, 2005 ). However, specific pharmacological SIRT2 inhibition with AK7 increased non-amylogenic APP processing by α-secretase and reduced processing by BACE1, down-regulating its expression in the hippocampus and ameliorating the AD-associated pathology in 3xTg-AD and APP/PS1 mice ( Wang Y. et al, 2020 ). Hence, SIRT1 and SIRT2 influence APP processing in opposing ways.…”

Section: Sirt1 and Sirt2 In Alzheimer’s Diseasementioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

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“…3F). Previous studies using a higher and longer dosage of AK7 have linked Sirt2 inhibition with reduced levels of Aβ in AD models (38) . However, we did not find changes in the in vivo levels of Aβ42 (Supp.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Palomer

Martín‐Flores

Jolly

et al. 2021

Preprint

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Growing evidence supports a role for deficient Wnt signalling in synapse degeneration in Alzheimer′s disease (AD). First, the Wnt antagonist DKK1 is elevated in the AD brain and is required for amyloidβ-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of particular interest due to their role in synapse formation and plasticity. Our analyses showed that FZD1 and FZD7 mRNA levels were reduced in the hippocampus of human preclinical AD (PAD) cases and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of inhibitory phosphorylation on Sirt2 in nuclear PAD samples and increased levels of the Sirt2 phosphatase PP2C, leading to hyperactive nuclear Sirt2 and favouring Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated Sirt2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose Sirt2 as an attractive target to ameliorate AD pathology.

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RTN4B‐mediated suppression of Sirtuin 2 activity ameliorates β‐amyloid pathology and cognitive impairment in Alzheimer's disease mouse model

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 43 publications

References 36 publications

Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

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