Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer's Disease.

ABSTRACT

Alzheimer's disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related (NOS3 and COX-2) gene expression in 3-4-month-old mice only, global (5mC)- and de novo DNA methylation (DNMT3a), HDAC3 expression and HDAC activity in 3-4-month-old mice; and SIRT1 expression and acetylated histone H3 protein levels in 8-9-month-old mice. Mass spectrometric analysis of Nosustrophine extracts revealed the presence of adenosylhomocysteinase, an enzyme implicated in DNA methylation, and nicotinamide phosphoribosyltransferase, which produces the NAD+ precursor, enhancing SIRT1 activity. Our findings show that Nosustrophine exerts substantial epigenetic effects against AD-related neurodegeneration and establishes Nosustrophine as a novel nutraceutical bioproduct with epigenetic properties (epinutraceutical) that may be therapeutically effective for prevention and early treatment for AD-related neurodegeneration.