Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperRegulated expression of neuronal SIRT1 and related genes by aging and neuronal β2-containing nicotinic cholinergic receptors

Longevity genes attenuate the aging process, but their expression in the brain during aging remains unknown. Loss of the majority of heteromeric brain nicotinic acetylcholine receptors (nAChRs) results in premature brain aging, and altered regulation of longevity genes could be involved. Using in situ hybridization, the expression of SIRT1, Ku70, Nampt, p53, forkhead Box O3 (FoxO3), and mitochondria uncoupling protein 5 (UCP5) was determined in neocortex and hippocampus of young adult 3-month and middle-aged 18-month-old wild-type (WT), and age-matched mice lacking β2* heteromeric nAChRs (β2−/−). Age-related structural changes were detected in WT mice. In particular, cortical thickness was decreased but neuronal density increased, and hippocampal volume increased with age. In contrast, young β2−/− mice exhibited increased cortical neuronal density, and with age, cortical thickness decreased more dramatically, and hippocampal volume did not increase. Thus, young β2−/− mice exhibited cortical signs of aging, and aging was accelerated at 18 months. The longevity genes probed exhibited similar expression patterns in frontal brain structures, with strong expression in hippocampus, medial habenula (MHb), and cortex. In WT mice, age significantly decreased expression of all genes except SIRT1 in cortical structures, and a similar pattern was detected in the MHb. Genotype had no effect on expression in young adults in either cortex or MHb, but increased mRNA expression of SIRT1, Nampt, and Ku70 was detected in cortex, hippocampus, and MHb of aged β2−/− mice compared with WT mice. This is the first study to determine age-related expression of survival genes in forebrain areas. Although, structural changes indicative of accelerated aging are evident in young β2−/− mice, the data suggest that nAChRs do not directly regulate expression of survival genes. However, loss of β2* nAChRs could result in augmented cellular stress, which indirectly increases expression of SIRT1, Nampt, and Ku70 as an adaptive response to provide protection against neurodegeneration.

▶We describe detectable changes in cortex of young adult β2−/− mice compared with WT. ▶Increased age-related changes in cortex and hippocampus of 18-month-old β2−/− mice. ▶First description of mRNA expression for Nampt, Ku70, and p53 in adult mouse brain. ▶Strong signal for SIRT1, Nampt, Ku70, p53, Foxo3, UCP5 in cortex, hippocampus, MHb. ▶Decreased expression in middle-age 18-month-old WT mice.