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

• Published in: Molecular neurobiology Vol. 58; no. 4; pp. 1769 - 1781
• Main Authors: Kocinaj, Altin, Chaudhury, Tabassum, Uddin, Mohammed S., Junaid, Rashad R., Ramsden, David B., Hondhamuni, Geshanthi, Klamt, Fábio, Parsons, Linda, Parsons, Richard B.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2021; Springer Nature B.V
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer's disease; Biomedical and Life Sciences; Biomedicine; Case-Control Studies; Cell Biology; Cerebellum; Cerebellum - enzymology; Cerebellum - pathology; Confocal microscopy; Disease control; Drug development; Female; Hippocampus; Hippocampus - enzymology; Hippocampus - pathology; Humans; Immunohistochemistry; Male; Methyltransferase; Middle Aged; Movement disorders; N-Methyltransferase; Neurobiology; Neurodegenerative diseases; Neurology; Neuronal-glial interactions; Neurons - enzymology; Neurons - pathology; Neurosciences; Nicotinamide N-methyltransferase; Nicotinamide N-Methyltransferase - metabolism; Original; Original Article; Parkinson's disease; Temporal lobe; Temporal Lobe - enzymology; Temporal Lobe - pathology; Western blotting; Therapies; methyltransferase; Overexpression; Alzheimer’s disease; Nicotinamide; Pathogenic process; Homocysteine; Stress response; Nicotinamide N-methyltransferase
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-020-02259-9

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.