No abstract

Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the ␤-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to 5-androstene-3␤,17␤-diol and to 7␣-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of ␤-amyloid deposits.

No abstract

No abstract

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology including β-amyloid accumulation, gliosis and behavioral impairment were examined under both early intervention (7 month-old young-adult male mice with low pathology) and treatment (24 month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young adult mice, but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in non-transgenic mice. These findings suggest TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

Hormonal and locally produced steroids act in the nervous system as neuroendocrine regulators, as trophic factors and as neuromodulators and have a major impact on neural development and function. Glial cells play a prominent role in the local production of steroids and in the mediation of steroid effects on neurons and other glial cells. In this review, we examine the role of glia in the synthesis and metabolism of steroids and the functional implications of glial steroidogenesis. We analyze the mechanisms of steroid signaling on glia, including the role of nuclear receptors and the mechanisms of membrane and cytoplasmic signaling mediated by changes in intracellular calcium levels and activation of signaling kinases. Effects of steroids on functional parameters of glia, such as proliferation, myelin formation, metabolism, cytoskeletal reorganization, and gliosis are also reviewed, as well as the implications of steroid actions on glia for the regulation of synaptic function and connectivity, the regulation of neuroendocrine events, and the response of neural tissue to injury. © 2006 Wiley‐Liss, Inc.

No abstract

No abstract