We have previously shown that the expression of nicotinamide N-methyltransferase (NNMT) is significantly increased in the brains of patients who have died of Parkinson’s disease (PD). In this study, we have compared the expression of NNMT in post-mortem medial temporal lobe, hippocampus and cerebellum of 10 Alzheimer’s disease (AD) and 9 non-disease control subjects using a combination of quantitative Western blotting, immunohistochemistry and dual-label confocal microscopy coupled with quantitative analysis of colocalisation. NNMT was detected as a single protein of 29 kDa in both AD and non-disease control brains, which was significantly increased in AD medial temporal lobe compared to non-disease controls (7.5-fold, P < 0.026). There was no significant difference in expression in the cerebellum (P = 0.91). NNMT expression in AD medial temporal lobe and hippocampus was present in cholinergic neurones with no glial localisation. Cell-type expression was identical in both non-disease control and AD tissues. These results are the first to show, in a proof-of-concept study using a small patient cohort, that NNMT protein expression is increased in the AD brain and is present in neurones which degenerate in AD. These results suggest that the elevation of NNMT may be a common feature of many neurodegenerative diseases. Confirmation of this overexpression using a larger AD patient cohort will drive the future development of NNMT-targetting therapeutics which may slow or stop the disease pathogenesis, in contrast to current therapies which solely address AD symptoms.

Parkinson’s disease is characterised by the deposition of α-synuclein, which leads to synaptic dysfunction, the loss of neuronal connections and ultimately progressive neurodegeneration. Despite extensive research into Parkinson’s disease pathogenesis, the mechanisms underlying α-synuclein mediated synaptopathy have remained elusive. Several lines of evidence suggest that altered NAD+ metabolism might be causally related to synucleinopathies, including Parkinson’s disease. NAD+ metabolism is central to the maintenance of synaptic structure and function. Its synthesis is mediated by nicotinamide mononucleotide adenylyltransferases (NMNATs), but their role in Parkinson’s disease is not known. Here we report significantly decreased levels of NMNAT3 protein in the caudate nucleus of patients who have died with Parkinson’s disease which inversely correlated with the amount of monomeric α-synuclein. The detected alterations were specific and significant as the expression levels of NMNAT1, NMNAT2 and sterile alpha and TIR motif containing 1 were not significantly different in Parkinson’s disease subjects compared to controls. To test the functional significance of these findings, we ectopically expressed wild-type α-synuclein in retinoic acid-differentiated dopaminergic SH-SY5Y cells which resulted in decreased levels of NMNAT3 protein plus a neurite pathology which could be rescued by FK866, an inhibitor of nicotinamide phosphoribosyltransferase that acts as a key enzyme in the regulation of NAD+ synthesis. Our results establish, for the first time, NMNAT3 alterations in Parkinson’s disease and demonstrate in human cells that this phenotype together with neurite pathology is causally related to α-synucleinopathy. These findings identify alterations in the NAD+ biosynthetic pathway as a pathogenic mechanism underlying α-synuclein mediated synaptopathy.