NAD regulates mitochondrial autophagy and is involved in the protective mechanism of Alzheimer's disease
Alzheimer's disease (AD) is A central nervous system degenerative disease characterized by progressive memory loss and cognitive impairment, characterized by extracellular amyloid beta (A) deposition and intracellular hyperphosphorylated tau tangles. Studies have shown that mitochondrial functional defects are closely related to neurodegenerative diseases such as AD. Swerdlow et al. (2004) proposed the "mitochondrial cascade hypothesis", suggesting that mitochondrial functional defects and increased oxidative stress occur in the early stage of AD, which is an upstream event of A and neurofibrillary tangles formation and is A major factor affecting the pathology of late AD. Recent studies have shown that nicotinamide adenine dinucleotide (NAD+) plays an important role in the development of AD by maintaining the balance between mitochondrial biogenesis and mitochondrial autophagy, affecting the health and survival of neurons.
1. Basic concepts of mitochondrial autophagy and NAD+
NAD+:NAD+ is not only a coenzyme in y REDOX, but also a key coenzyme in a variety of enzymes in the Sirtuin family, including deacetylase, DNA repair protein polyadenosine diphosphate ribose polymerase (PARP) and cyclic ADP ribose hydrolases CD38 and CD157, and is involved in various physiological activities such as mitochondrial autophagy, cell DNA damage repair and calcium homeostasis.
2.1 Study of NAD+-SIRT1 pathway
Serine/threonine kinase plays a role in DNA repair and a variety of cell homeostasis pathways. In interspecies research, whether the original generation of neurons in rats, c. elegans or ataxia in mice, capillary expansion results show that capillary dilated ataxia (ATM) loss induced mutation of mitochondrial dysfunction and PARP1 activation, NAD + and consumption, the SIRT1 deactivation caused by mitochondrial autophagy dysfunction. After NAD+ supplementation, DNA repair defects and mitochondrial dysfunction of ATM protein kinase-deficient neurons were significantly improved, and the health and life span of ATM-/- model mice were also improved. As a mitochondrial outer membrane protein, the cycle-related protein 1 in worms is a direct homologous to BNIP3/NIX in mammals, and has recently been proved to be a major participant in mitochondrial autophagy. Studies have found that activation of THE NAD+-SIRT1 pathway can up-regulate DCT-1 and activate autophagy-related proteins to restore mitochondrial autophagy. In addition, NAD+-SIRT1 induces autophagy and/or mitochondrial autophagy by activating ADENosine activated protein kinase (AMPK), which promotes ULK1 phosphorylation of ATG1. Similarly, NAD+-SIRT1 can activate AMPK in primary rat cortical neurons to phosphorylate the tuberous sclerosing complex at SER1387, inhibit mammalian target of rapamycin (mTOR), and induce autophagy and/or mitochondrial autophagy.
Studies have reported that aggregation of human wild-type full-length Tau in cells can increase the mitochondrial membrane potential by directly inserting into the mitochondrial membrane, resulting in damage of the PINK1/Parkin pathway, thereby inducing mitochondrial autophagy disorders. Study in new AD mice model of defects in DNA repair, NAD + levels drop, SIRT3 activity decline, supplementary NAD + precursor nicotinamide SIRT3 activity after RNA nucleoside, nerve inflammation, synaptic transmission, tau protein phosphorylation, DNA damage, as well as learning and memory function improved significantly, prompt NAD + - SIRT3 pathway mediated mitochondrial function is impaired in neuropathy caused by DNA damage increase rational change play an important role. In A similar study, 3xTgAD mice treated with nicotinamide for 8 months maintained mitochondrial integrity and enhanced lysosomal/autolysosomal degradation to reduce autophagic volume accumulation, leading to A and hyperphosphorylated Tau protein reduction in the hippocampus and cerebral cortex, resulting in improved cognitive function. Since NAD+ -SIRt1 up-regulates autophagy through deacetylation of major autophagy proteins Atg5, Atg7, and Atg8, autophagy and/or mitochondrial autophagy up-regulates the removal of neuronal tangles of A plaque and hyperphosphorylated Tau protein, improving mitochondrial function and neuronal survival. Therefore, supplementation of NAD+ and its precursors may play a protective role in age-related diseases such as AD. A meta-analysis showed that the incidence of MILD cognitive impairment in China was relatively high, reaching 12.7%. If patients with mild cognitive impairment do not receive timely and effective intervention, they will have a higher risk of developing AD. From mild cognitive impairment to AD, autophagy and other mitochondrial dysfunction are triggers that promote A and Tau protein aggregation. However, NAD+ and its precursor substances can regulate mitochondrial autophagy through multiple pathways such as SIRT1 and SIRT3, remove pathological changes related to AD such as damaged mitochondria, A and Tau proteins, and improve cognitive dysfunction. Therefore, NAD+ precursor therapy is expected to be a new strategy for the prevention and treatment of AD.