High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease

Abstract

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.

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

“…Its activity regulates NAD+ synthesis via the reduction in available nicotinamide [37]. NNMT expression is increased in several disease pathologies, including neurodegenerative diseases such as Alzheimer's [38] and Parkinson's disease [39,40], hepatic cirrhosis [41], atherosclerosis [42], pulmonary hypertension [43], acute hepatitis [44], fatty liver disease [45], obesity and metabolic syndrome [46,47], peripheral occlusive arterial disease [48] and chronic obstructive pulmonary disease [49]. Several thousand single nucleotide polymorphisms (SNPs) have been reported in the NNMT gene, many of which have been linked to disease and other biochemical outcomes, a full review of which has been published elsewhere [50].…”

Resilience in Long-Term Viral Infection: Genetic Determinants and Interactions

“…In the present study, we compared sequence variation across the CC founder strains with a focus on those variants specific to the WSB/EiJ founder (associated with the resilient response group for Nnmt ) and A/J founder (associated with the susceptible group for Nnmt ). Nnmt has been associated with neurodegeneration and Parkinsonian behavior in humans [ 113 , 114 ] and the model organism C. elegans [ 115 ], and more recently with Alzheimer’s disease [ 116 ]. Dysregulation of Nnmt is recognized as a contributor to neurological diseases, cancers, and obesity (e.g., [ 116 , 117 , 118 , 119 , 120 ]).…”

“…Nnmt has been associated with neurodegeneration and Parkinsonian behavior in humans [ 113 , 114 ] and the model organism C. elegans [ 115 ], and more recently with Alzheimer’s disease [ 116 ]. Dysregulation of Nnmt is recognized as a contributor to neurological diseases, cancers, and obesity (e.g., [ 116 , 117 , 118 , 119 , 120 ]). In fact, at least one Nnmt sequence variant has been connected with neurological disease in humans [ 119 ].…”

Exploring Unconventional SAM Analogues To Build Cell‐Potent Bisubstrate Inhibitors for Nicotinamide N‐Methyltransferase

“…NNMT transfers the methyl group from S ‐adenosyl‐ L ‐methionine (SAM) to nicotinamide (NAM) while generating S ‐adenosyl‐ L ‐homocysteine (SAH) and N 1‐methyl nicotinamide (MNA) [16, 17] . Elevated levels of NNMT have been implicated in various cancers, metabolic, cardiovascular, and neurodegenerative diseases [3–5, 7, 18–22] . Recently, we reported a potent and selective bisubstrate inhibitor LL320 for NNMT ( K i =1.6 nM) by covalently connecting N4‐adenosyl‐2,4‐diaminobutanoic acid with a benzamide [12] .…”