Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
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 essentia...
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Published in | Cell death & disease Vol. 12; no. 7; pp. 651 - 10 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
25.06.2021
Springer Nature B.V Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-021-03926-y |