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Parp mutations protect from mitochondrial toxicity in Alzheimer's disease.

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Yu, Yizhou 
Celardo, Ivana 
Loh, Samantha HY 


Alzheimer's disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer's disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer's disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer's disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer's disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes such as PARPs are potential therapies for Alzheimer's disease.



Alzheimer Disease, Amyloid beta-Peptides, Animals, Animals, Genetically Modified, Behavior, Animal, Disease Models, Animal, Drosophila Proteins, Drosophila melanogaster, Humans, Metabolome, Metabolomics, Mitochondria, Motor Activity, Mutation, NAD, Nerve Degeneration, Neurons, Niacinamide, Poly (ADP-Ribose) Polymerase-1, Polymorphism, Single Nucleotide

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Cell Death Dis

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Springer Science and Business Media LLC
Medical Research Council (MC_U132674518)
Medical Research Council (MC_UU_00025/3)