Niacin (also called vitamin B3 or vitamin PP) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). found in AD patients and its enzymatic activity is related to clearance of tau protein . Lastly, fluctuations in NAD+ availability can reduce AD pathology, also by modulating SIRT1 activity and slowing aging and age-associated diseases [166,167]. Several studies have underlined the key role of SIRTs in AD prevention: in particular, deacetylase activity of SIRT1 has been shown to support the non-amyloidogenic pathway of AD , and to counteract phenomena, like neuroinflammation, oxidative stress and mitochondrial dysfunction, contributing to, and aggravating, AD [144,145]. 8. Parkinsons Disease Parkinsons disease (PD) is a progressive disorder seen as a degeneration of dopaminergic neurons inside the substantia nigra, whose primary hallmarks are irregular aggregation from the -synuclein proteins, inhibition of mitochondrial respiratory complicated 1, oxidative neuroinflammation and stress. Because just 5C10% of PD instances could be ascribed to hereditary predisposition, many environmental elements might are likely involved in sporadic types of PD . Among them, supplement B3 can be a promising precautionary and therapeutic element (Desk 1), as it could alleviate particular types of early-onset PD symptoms. NAD+ amounts, certainly, fall in individuals with PD and, conversely, raising niacin intake can boost dopamine synthesis Regadenoson in the striatum and restore ideal NAD+/NADH ratio necessary for the experience of mitochondrial complicated 1 . Large niacin amounts may also sequester changeover metallic ions (including iron) that Regadenoson always accumulate alongside the event of aggregated misfolded protein [149,150]. Furthermore, ideal degrees of supplement B3 are necessary for reducing oxidative neuroinflammation and tension, also implicated in PD pathogenesis: low dosages of niacin alter macrophage polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenothype, while exogenous NADPH suppresses oxidative tension and glia-mediated neuroinflammation [151,152]. Neurons will be the just cells of the mind expressing NNMT that appears to play a significant part in sustaining neuron homeostasis . Despite several investigations, the precise cause-effect relationship between PD and NNMT neuropathogenesis remains unclear. Some authors make reference to NNMT like a risk element for PD, since its amounts are raised in the cerebrospinal midbrain and liquid dopamine neurons of PD individuals [153,154]. Large NNMT activity can be connected with low activity of mitochondrial complicated 1, offering a web link with mitochondrial dysfunction triggering neurodegeneration [154 therefore,155]. It really is noteworthy that gene; this finding suggests that neurotoxicity associated with mitochondrial defects may be prevented by modulating NAD+ salvage metabolism in order to enhance NAD availability . 9. Huntingtons Disease Huntingtons disease (HD) is an autosomal dominant neurodegenerative disease characterized by typical progressive motor disturbances (involuntary movements of face and body, abnormalities in gait, posture and balance), psychiatric disorders (dementia) and other cognitive impairments . HD is caused by a CAG expansion in the gene encoding for huntingtin (htt), located on chromosome 4; normally, the gene contains up to 35 CAG repeats, while in HD it has more than 36 CAG repeats that produce a mutant protein, with an abnormally long polyglutamine repeat (polyQ), responsible Regadenoson for the selective striatal degeneration of medium-sized spiny neurons and cerebral cortex . In neurons, Regadenoson mutant htt protein aggregates, thus critically damaging cellular integrity by impairing proteostasis network, mitochondrial function and energy balance, transcriptional regulation, synaptic function and axonal transport . From metabolomic studies, it has emerged that the metabolite (e.g., Trp, Bnip3 kynurenine, quinolinic acid and 3-hydroxykynurenine) content and activity of KP enzymes are pathologically altered in experimental HD models and human patients [109,110]. Moreover, in a model of HD, disease progression has been found to be associated with a reduction in NAD levels, suggesting that dietetic or pharmacological supplementation of niacin (or its derivatives) may be useful in HD patients . Several studies, indeed, have put forward a beneficial effect of vitamin B3 in HD (Table 1): for example, nicotinamide is Regadenoson protective against toxicity of polyQ proteins in HD models , while, in transgenic mouse models, it restores brain-derived neurotrophic factor (BDNF) protein levels, increases acetylated peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), a master regulator of mitochondrial biogenesis, and improves motor deficits.