Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia and a major risk factor for developing other diseases [1,2,3,4]
Identification of a metabolic signature linked to nicotinate and NAM metabolism in flies expressing toxic Aβ To study the metabolic alterations caused by the expression of toxic Aβ in an in vivo model, we conducted a global analysis of the metabolome of adult flies expressing a secreted form of Aβ-Arc [9] in neurons
We found that Aβ-Arc causes significant alterations in the nicotinate and NAM metabolism pathway, an upregulation in several precursors of the coenzyme NAD+ belonging to the tryptophan metabolism pathway and a decrease in NAD+, which is essential for generating energy in mitochondria (Fig. 1B, C)
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and a major risk factor for developing other diseases [1,2,3,4]. Familial AD is associated with the accumulation of a toxic form of the amyloid-β (Aβ) peptide in the brain [5,6,7,8]. Animal models of AD in the fruit fly Drosophila melanogaster were generated by expressing toxic human Aβ in the fly’s neurons [9]. The neuronal expression of the disease-associated Aβ (1-42), with an Arctic mutation (Glu22Gly) (Aβ-Arc), resulted in its accumulation in the neuronal cells. The accumulation of Aβ-Arc in turn causes neurodegeneration and premature neuronal cell death, recapitulating pathological features of AD in humans (reviewed in [10]). Flies are a powerful animal model for studying the mechanisms of neurodegeneration and the identification of novel preventive strategies for this disease [11]
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