Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

• Published in: Cell death & disease Vol. 12; no. 7; pp. 651 - 10
• Main Authors: Yu, Yizhou, Fedele, Giorgio, Celardo, Ivana, Loh, Samantha H. Y., Martins, L. Miguel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.06.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 14/19; 14/28; 631/378/1689/1283; 631/378/1934; 631/45/320; 64/24; Adenine; Age; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Animals, Genetically Modified; Antibodies; Behavior, Animal; Bioavailability; Biochemistry; Bioenergetics; Biomedical and Life Sciences; Cell Biology; Cell Culture; Disease Models, Animal; DNA repair; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Humans; Immunology; Life Sciences; Metabolome; Metabolomics; Mitochondria; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - ultrastructure; Mitochondrial DNA; Motor Activity; Mutation; NAD; NAD - metabolism; Nerve Degeneration; Neurodegeneration; Neurodegenerative diseases; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Niacinamide - pharmacology; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Polymorphism, Single Nucleotide; Ribose; Supplements; Toxicity; Vitamin B
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03926-y

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.