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Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

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If you have a question about this talk, please contact Katharina Zuhlsdorff.

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 over-expressing 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 PAR Ps are potential therapies for Alzheimer’s disease.

This talk is part of the CamBRAIN Virtual Journal Club series.

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