Mechanisms of neuronal death in brain aging and alzheimer's disease: Role of endocrine‐mediated calcium dyshomeostasis

Abstract

This paper reviews evidence that brain aging and Alzheimer's disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (GC) neurotoxicity. Moreover, recent electrophysiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium channels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease.

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…These three alterations are not necessarily independent phenomena. A well documented example concerns the hypercorticism and increased GR affinity observed in the hippocampus of Fischer rats at old age, which correlates well with a GR-mediated increase of the Ca-influx through voltage-activated calcium channels (Kerr et al, 1992.…”

“…Down regulation of GRs in brain and pituitary is commonly observed in aged Wistar and Fischer-344 rats, which show obvious signs of hypercorticism (Reul et al, 1988;Landfield et al, 1992; one report showed an impaired upregulation of the GRs (Eldridge et al. 1989).…”

“…While the first needs to be investigated, evidence for the second possibility was recently supplied. (~urrent clamp investigations revealed that the high threshold Ca-spike in CA1 pyramidal neurons is enhanced in amplitude and duration in neurons from rats with an intact HPA-axis vs ADX rats (Kerr eta/., 1989); similarly, high doses of the GR agonist RU 28362 administered in t,itro increased the Ca-spike (Kerr et al. 1992).…”

“…This is supported by a recent study showing that both basal and KA-induced elevations in [Ca], are enhanced by prolonged treatment of hippocampal cultures with high corticosteroid concentrations (Elliot and Sapolsky, , 1993, a phenomenon that not only involves changes in Ca-influx but also in Ca-extrusion. In addition, Ca-entry through voltage gated Cachannels, which open secondary to the amino acid-mediated depolarization, is also elevated when GRs are activated (Kerr et al_ 1992;Karst et al, 1994). Interestingly, synaptic transmission in slices from ADX rats, i.e.…”

Apoptotic cell death induced by optic nerve lesion in the neonatal rat

“…A recent hypothesis formulated by Cheng and Mattson proposes that the mechanisms by which trophic factors, such as NGF and bFGF, exert their protective effect on injured neurons could be through a stabilization in calcium homeostasis (Cheng and Mattson,199 1). The notion that disparate types of neuronal injuries are associated with calcium deregulation (Mattson, 1990;Strautman et al, 1990;Choi, 1992;Heizmann and Braun, 1992;Landfield et al, 1992) and the observation that their effects can be partially prevented by trophic factors (Fisher et al, 1987, 199 1;Cheng and Mattson, 1991) suggest that these different pathologies could share similar mechanisms of degeneration. Our findings of apoptosis in axotomized retinal ganglion cells raise the question as to whether a similar type of active, apoptotic death could occur in other neurodegenerative conditions.…”