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 PARPs are potential therapies for Alzheimer’s disease.

Parkinson’s disease is affects millions of people around the world. The disease is characterized by typical movement defects that are caused by the loss of dopaminergic neurons, but several very debilitating non-motor symptoms occur more than 10 years before the motor symptoms. I will discuss how we study these non-motor symptoms including sleep disturbances and olfactory defects using large collections of knock in fruit flies that model the numerous familial forms of Parkinson’s disease as well as using human iPS cells from patients. A common emerging theme are defects in protein homeostasis that in specific neuronal cell types, cause cellular defects that explain the Parkinson-relevant phenotypes. Our work reveals the mechanisms that cause early defects in Parkinson’s disease and it opens therapeutic avenues to start tackling this disease.