title: Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence.
abstract: Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.
authors: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors: Nady
authors: N
authors: Braidy
authors: Anne
authors: A
authors: Poljak
authors: Ross
authors: R
authors: Grant
authors: Tharusha
authors: T
authors: Jayasena
authors: Hussein
authors: H
authors: Mansour
authors: Tailoi
authors: T
authors: Chan-Ling
authors: Gilles J
authors: GJ
authors: Guillemin
authors: George
authors: G
authors: Smythe
authors: Perminder
authors: P
authors: Sachdev
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004249:DNA Damage; D004579:Electron Transport; D005260:Female; D055785:Gene Knockdown Techniques; D015227:Lipid Peroxidation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D050050:Protein Carbonylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D051997:ADP-ribosyl Cyclase 1; C488368:Sirt1 protein, rat; D056564:Sirtuin 1