NAD ⁺ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING

Abstract

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS–STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS–STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS–STING in neuroinflammation and cellular senescence in AD.

Aging, Cellular Senescence, and Alzheimer’s Disease

“…Increased deposition of amyloid plaques extracellularly and accumulation of hyperphosphorylated tau proteins intracellularly are two pathological hallmarks of Alzheimer's disease [44,45]. Although the mechanisms underlying increased deposition of Aβ and phosphorylated tau proteins in the brain of LOAD patients are unknown, several mouse models that overexpress mutant human amyloid precursor protein (APP) or APP plus mutant human presenilin 1 or mutant form of human microtubule-associated protein tau P301S have been generated and used to study the mechanisms, whereby Aβ and hyperphosphorylated tau proteins promote AD pathophysiology [24,25,40,41,49,[70][71][72][73][74][75][76]. Emerging evidence from these animal studies indicates that increased Aβ and tau phosphorylation promote brain cell senescence and that cellular senescence plays a critical role in the neuropathology and memory decline in AD.…”

“…These mice display a significant increase in brain Aβ load and memory impairment and have been widely used as a murine model of familial AD. Emerging evidence shows that various types of brain cells, including oligodendrocyte precursor cells (OPCs), astrocytes, microglia, and neurons, express higher levels of senescence markers p16, p21, and SA-β-gal in these familial AD model mice [25,40,70,71] Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and is involved in many biological processes. Hou et al reported that, associated with a decline in NAD+ level in the brain, various types of brain cells in APP/PS1 mice displayed a senescence phenotype, including increased SA-β-gal activity, as well as increased p16 and p21 expression, [71].…”

“…Emerging evidence shows that various types of brain cells, including oligodendrocyte precursor cells (OPCs), astrocytes, microglia, and neurons, express higher levels of senescence markers p16, p21, and SA-β-gal in these familial AD model mice [25,40,70,71] Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and is involved in many biological processes. Hou et al reported that, associated with a decline in NAD+ level in the brain, various types of brain cells in APP/PS1 mice displayed a senescence phenotype, including increased SA-β-gal activity, as well as increased p16 and p21 expression, [71]. Treatment with NAD+ precursor nicotinamide riboside (NR) increased brain NAD+ level and reduced senescent cell number and neuroinflammation, suggesting that cellular senescence and neuropathological changes were observed in the brain of APP/PS1 mice may result from NAD+ deficiency [71].…”

“…Hou et al reported that, associated with a decline in NAD+ level in the brain, various types of brain cells in APP/PS1 mice displayed a senescence phenotype, including increased SA-β-gal activity, as well as increased p16 and p21 expression, [71]. Treatment with NAD+ precursor nicotinamide riboside (NR) increased brain NAD+ level and reduced senescent cell number and neuroinflammation, suggesting that cellular senescence and neuropathological changes were observed in the brain of APP/PS1 mice may result from NAD+ deficiency [71]. A causative relation between cellular senescence and neuropathophysiology in APP/PS1 mice has been well elaborated in another recent publication [25].…”

Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

“…Moreover, such studies may provide useful mechanistic insights to develop therapeutic opportunities against inflammation in aging and in age-related disorders. Indeed, evidence is emerging that the cGAS-STING pathway is malleable to modification by pharmacological intervention [ 226 ].…”