Neurobiology of aging
-
Neurobiology of aging · Jul 2006
Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice.
Cerebral amyloid angiopathy (CAA) is a prominent pathological feature of Alzheimer's disease and related familial CAA disorders. However, the mechanisms that account for the cerebral vascular accumulation of amyloid beta-peptide (A beta) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human A beta precursor (A betaPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular A beta. ⋯ However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant A beta in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type A beta. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant A beta in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type A beta in plasma. Together, these findings suggest that while wild-type A beta is readily transported out of brain into plasma, Dutch/Iowa mutant A beta is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.
-
Neurobiology of aging · Jun 2006
Comparative StudyReduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice.
Sensory neurons in aging mammals undergo changes in anatomy, physiology and gene expression that correlate with reduced sensory perception. In this study we compared young and aged mice to identify proteins that might contribute to this loss of sensation. We first show using behavioral testing that thermal sensitivity in aged male and female mice is reduced. ⋯ No change was measured in TRPV1 mRNA levels in DRG though TRPV1 protein appeared reduced in the DRG and peripheral nerves. The GFRalpha3 receptor, which binds the growth factor artemin and is expressed by TRPV1-positive neurons, was also decreased in the DRG of aged animals. These findings indicate that loss of thermal sensitivity in aging animals may result from a decreased level of TRPV1 and Nav1.8 and decreased trophic support that inhibits efficient transport of channel proteins to peripheral afferents.
-
Neurobiology of aging · Jul 2005
Comparative StudyAge-related metabolic changes in the upper brainstem tegmentum by MR spectroscopy.
Several neurodegenerative disorders have a profound metabolic and structural impact on the brainstem. MR spectroscopy provides metabolic information non-invasively and has the potential to characterize the changes associated with normal aging and differentiate them from neurodegenerative alterations. The present work was aimed at studying the upper brainstem tegmentum at the midbrain and pontine levels in 57 adult normal volunteers, aged 23-79 years, with long-echo time proton MR spectroscopy to evaluate possible regional differences and the effect of age. ⋯ In the midbrain, there was a linear decline of NAA and Cho with age in subjects over 50, most probably related to neuronal tissue loss. In the pons, such an aging effect was not observed, with subjects over 50 showing higher Cr and Cho than the under-50 subjects. Our findings provided evidence of regional differences and suggest different effects of age on the two studied brainstem segments, hitherto undescribed.
-
Neurobiology of aging · Jun 2005
Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors.
Caffeine, a non-selective adenosine receptor antagonist, has been suggested as a potential drug to counteract age-related cognitive decline since critical changes in adenosinergic neurotransmission occur with aging. In the present study, olfactory discrimination and short-term social memory of 3, 6, 12 and 18 month-old rats were assessed with the olfactory discrimination and social recognition tasks, respectively. ⋯ Acute treatment with caffeine or ZM241385, but not with DPCPX, reversed these age-related olfactory deficits. The present results suggest the participation of adenosine receptors in the control of olfactory functions and confirm the potential of caffeine for the treatment of aged-related cognitive decline.
-
Neurobiology of aging · May 2005
Comparative StudyAge- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders.
Accumulation of amyloid beta-protein (Abeta) is a fundamental feature of certain human brain disorders such as Alzheimer's disease (AD) and Down syndrome and also of the skeletal muscle disorder inclusion body myositis (IBM). Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between production and degradation. Although the proteolytic processes leading to Abeta formation have been extensively studied, less is known about the proteases that degrade Abeta, which include insulin-degrading enzyme (IDE) and neprilysin (NEP). ⋯ We further show that IDE is more oxidized in the hippocampus compared to the cerebellum of AD patients. In muscle, we find differential levels of IDE and NEP in fast versus slow twitch muscle fibers that varies with aging. These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.