Alzheimer's disease pathology is attenuated in a <scp>CD</scp>38‐deficient mouse model

Blacher, Eran; Dadali, Tulin; Bespalko, Alina; Haupenthal, Viola J.; Grimm, Marcus O.W.; Hartmann, Tobias; Lund, Frances E.; Stein, Reuven; Levy, Ayelet

doi:10.1002/ana.24425

Cited by 92 publications

(69 citation statements)

References 49 publications

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“…The recent development of potent and specific CD38 inhibitors (Escande et al, 2013; Haffner et al, 2015), together with the novel findings highlighting the role of NAD + replacement therapy and CD38 in age-related diseases such as hearing loss and Alzheimer’s (Prolla and Denu, 2014; Chini 2009; Blacher et al, 2015), indicate that CD38 inhibition combined with NAD precursors may serve as a potential therapy for metabolic dysfunction and age-related diseases.…”

Section: Discussionmentioning

confidence: 99%

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

et al. 2016

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Summary Nicotinamide Adenine Dinucleotide (NAD) levels decrease during aging, and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

et al. 2016

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“…Treatment of neural cells with a PARP1 inhibitor can protect them against mitochondrial dysfunction and cell death caused by Aβ [93]. APP/PS1 double mutant transgenic mice that lack CD38 exhibit reduced levels of A in their brains and improved learning and memory [94], consistent with NAD + depletion in promotion of amyloidogenesis in this mouse model of AD. The available data suggest that NAD + deficiency in AD, possibly caused by PARP1 activation due to increased oxidative stress-mediated DNA damage, leads to decreased sirtuin activity, decreased mitophagy, and mitochondrial dysfunction.…”

Section: Compromised Autophagy and Mitophagy In Admentioning

confidence: 99%

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

Kerr

Adriaanse

Greig

et al. 2017

Trends in Neurosciences

611

536

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Neurons affected in Alzheimer’s disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid β-peptide (Aβ) and Tau pathologies. Emerging findings suggest that the autophagy – lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impair mitophagy. Interventions that bolster mitochondrial health and/or stimulate mitophagy may therefore forestall the neurodegenerative process in AD.

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“…Several inhibitors were shown to have the ability to raise NAD levels and improve glucose homeostasis and fatty acid metabolism in vivo (417,420). CD38 was shown to play a role in certain diseases related to aging, including Alzheimer's disease (421).…”

Section: Parp Nad ؉ Metabolism and Inflammationmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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Alzheimer's disease pathology is attenuated in a CD38‐deficient mouse model

Abstract: CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.

Cited by 92 publications

References 49 publications

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

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