Free intracellular calcium in aging and Alzheimer's disease

Brain cells of aged mice exhibit distinct alterations of [Ca2+]i regulation resulting in lower levels of [Ca2+]i after stimulation. These alterations are probably more related to disturbances of mechanisms regulating transmembraneous Ca2+ fluxes than to mechanisms of intracellular Ca2+ release and storage. Comparable although not identical disturbances of [Ca2+]i regulation are present in mouse, rat, and human lymphocytes. Accordingly, one is tempted to speculate that in the human brain similar alterations of [Ca2+]i regulation might be present in aging as found in the aged mouse and rat brain. Since the downregulation of [Ca2+]i levels in aged brain cells seems to be accompanied by an enhanced intracellular sensitivity for changes of [Ca2+]i, both divergent alterations might compensate each other under normal conditions. However, it seems quite conceivable that the ability of the Ca2+ signal transduction pathway to adopt to periods of over-or understimulation (e.g., hypoxia, stress) might be disturbed in the aging brain. One of those conditions of additional alterations of [Ca2+]i regulation might be AD. Although we did not see AD-specific changes of [Ca2+]i regulation per se, the effect of beta A4 on cellular [Ca2+]i regulation was significantly and specifically disturbed in AD. It is not unlikely that a small, but long lasting (years or even decades) alterations of cellular [Ca2+]i regulation by beta A4, which is a product of normal brain metabolism, might finally contribute to the severe neuronal damage seen during the disease

Zur Kalziumhypothese der Hirnalterung

The "calcium hypothesis of brain aging" assumes that a small increase in free intra-cellular calcium concentration ([Ca2+]i) over years or decades finally leads to brain lesions similar to the short [Ca2+]i overload following one acute event (e.g., stroke). Recent data are reviewed that disprove the hypothesis in this rather simple form. Studies on brain cells of experimental animals as well as on animal and human blood cells suggest that [Ca2+]i is reduced rather than elevated in brain aging. However, probably as compensation, aging seems to lead to enhanced sensitivity of the brain (or of calcium-dependent mechanisms in the brain) to changes in [Ca2+]i. Under normal conditions, both alterations seem to compensate each other. However, under situations of additional stress leading to elevated [Ca2+]i (hypoxia, hypoglycemia), aged brain cells might be more vulnerable because of a reduced ability to down-regulate [Ca2+]i. In contrast to these typical changes in the aging, very little evidence exists that [Ca2+]i is also changed in Alzheimer's disease. On the other hand, recent evidence suggests that the modulation of [Ca2+]i by beta-amyloid is specifically altered in this disease, but the pathogenetic significance of this observation is not yet finally understood

Region-specific downregulation of free intracellular calcium in the aged rat brain

Age-related changes in resting levels of the free intracellular calcium concentration ([Ca2+]i) as well as alterations of the rise in [Ca2+]i following depolarization have been investigated in acutely isolated brain cells of various regions of the rat brain. Characterization of the Ca2+ responses following KCl depolarization in the hippocampus, cortex, striatum, and cerebellum of young rats revealed significant regional differences in the basal [Ca2+]i level as well as in the KCl-induced rise in [Ca2+]i. However, there was no correlation between both parameters. Resting [Ca2+]i as well as Ca2+ responses after depolarization were lower in the hippocampus and cortex of the aged animals, but not in the striatum or cerebellum. It is concluded that the Ca2+ homeostasis in the first two regions is specially susceptible to the aging process, resulting in a downregulation of [Ca2+]i, probably as a consequence of an enhanced sensitivity of mechanisms regulating transmembraneous Ca2+ fluxes. The cellular Ca2+ homeostasis was altered in a comparable way in rat spleenocytes. The rise in [Ca2+]i in the aged animals following stimulation of lymphocytes with the mitogen phytohemagglutinin (PHA) was significantly reduced in the plateau phase, which is maintained by Ca2+ influx mechanisms. The data indicate that age-related disturbances of the cellular Ca2+ homeostasis may be present in different cell types and seem to affect mainly transmembraneous Ca2+ flux much more than intracellular Ca2+ release

Down-regulation of free intracellular calcium in dissociated brain cells of aged mice and rats

Age-related changes in resting levels of the free intracellular calcium concentration ([Ca2+]i) as well as alterations of the rise in [Ca2+]i following depolarization have been investigated in acutely isolated cells of the mouse brain and of various regions of the rat brain. Resting [Ca2+]i as well as Ca2+ responses after depolarization were lower in brain cells of aged mice and in hippocampus and cortex cells, but not striatum or cerebellum cells of aged rats. It is concluded that the Ca2+ homeostasis is specially susceptible to the aging process in some brain regions only, resulting in a down regulation of [Ca2+]i probably as a consequence of an enhanced sensitivity of mechanisms regulating [Ca2+]i. This speculation was confirmed by an enhanced sensitivity of Ca(2+)-stimulated phospholipase C activity in the aging mouse brain. The alterations of the central Ca2+ homeostasis in the mouse and the rat were paralleled by comparable changes of [Ca2+]i in spleenocytes of both species in aging. The rise of [Ca2+]i after stimulation with the mitogen phytohemagglutinin (PHA) was significantly reduced in the plateau phase, which is maintained by Ca2+ influx mechanisms. Moreover, a reduced Ca2+ response was also found after stimulation of the cells with the Ca2+ ionophore A23187. The data may indicate that comparable disturbances of the Ca2+ homeostasis occur in central and peripheral cells and that these alterations mainly affect transmembraneous Ca2+ fluxes rather than Ca2+ release from intracellular stores. These alterations may be compensated under normal conditions. However, in situations of additional stress like ischemia or hypoglycemia, the preexisting alterations of Ca2+ homeostasis may result in a reduced capacity for adaptation. This assumption was supported by observations indicating that the down-regulation of [Ca2+]i after subchronic treatment with nimodipine (20 mg/kg, 14 days) was less in brain cells of aged than of young mice