NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway

Abstract

Background Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. Methods The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation. Results NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia. Conclusions NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.

Ligustilide Improves Cognitive Impairment via Regulating the SIRT1/IRE1α/XBP1s/CHOP Pathway in Vascular Dementia Rats

“…It can reduce neuronal loss, suppress inflammation, and inhibit apoptosis and oxidative stress in the hippocampus of VaD rats [ 46 – 48 ]. Previous studies have shown that chronic cerebral hypoperfusion leads to a downregulation of SIRT1 in the brain of VaD rats, which is similar to our study [ 15 , 47 ]. However, oral administration of LIG enhanced the expression of SIRT1 in the cortex and the hippocampus of VaD rats.…”

“…Sirtuin1 (SIRT1), a NAD+-dependent deacetylase, is thought to participate in the regulation of cellular senescence and aging [ 12 ]. Some studies have shown that increasing the expression of SIRT1 could improve cognitive impairment in VaD rats by promoting angiogenesis, anti-inflammatory, antioxidant, and antiapoptosis [ 13 – 15 ]. Interestingly, recent studies have reported that the activation of SIRT1 could alleviate cell damage caused by ER stress [ 16 , 17 ].…”

A Peek into Pandora’s Box: COVID-19 and Neurodegeneration

“…Increased PGC-1α expression was shown to reduce NLRP3 inflammasome activation, proinflammatory cytokine production, and decrease neuroinflammation and depression-like behavior [ 239 , 240 ]. Several compounds have been identified in other models of neurological damage that reduce neuroinflammation and oxidative damage through AMPK/PGC-1α– or SIRT1/PGC-1α–mediated pathways and improve cognitive outcomes [ 241 , 242 , 243 , 244 ]. Melatonin is a hormone involved in control of the sleep–wake cycle and has anti-inflammatory, anti-oxidative, and mitochondrial protective properties.…”

Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts

“…In a rat model of chronic cerebral hypoperfusion (a major cause of vascular dementia), direct supplementation with NAD + (intraperitoneal injection of 250 mg/kg/day for 8 weeks) significantly ameliorated the impairment of learning and memory [ 11 ]. In another study, the cognitive impairment caused by chronic cerebral hypoperfusion was shown to be improved in mice by treatment with NAM (intraperitoneal injection of 200 mg/kg/day for 30 days), with significant benefits to learning, memory, anxiety, and depression-like behaviours [ 23 ].…”

“…Additionally, it is a key substrate for ADP-ribosylation by poly-ADP-ribose polymerase (PARP) enzymes, protein deacetylation by sirtuins, and cyclic ADP-ribose (cADPR) production by CD38 and CD157 [ 5 ]. Numerous mechanisms have been proposed to explain how supplementation in support of NAD + levels can achieve neuroprotection, with evidence from different contexts supporting reduced oxidative stress [ 6 ], lowered protein aggregation [ 7 ], anti-inflammatory effects [ 8 ], the stimulation of neuroprotective HCA2 macrophages [ 9 ], the blocking of autophagy [ 10 ], and the amelioration of mitochondrial damage and dysfunction [ 11 ]. This evidence leads to the conclusion that the relevant pathway is complex and likely multifactorial.…”