E.C. Toescu, J. Xiong

Normal brain ageing is associated with a degree of functional impairment of neuronal activity that results in a reduction in memory and cognitive functions. One hypothesis proposed to explain these age-dependent changes in neuronal activity is the "Ca2+ hypothesis of ageing". However, recent experiments using cerebellar brain slices [1] show that in resting conditions there are few differences in the main parameters of Ca2+ homeostasis between young, mature and aged neurones. Differences become manifest only during neuronal stimulation, and are mainly manifested as a decrease in the rate of [Ca2+]i recovery following stimulation. More recent experiments show that this decrease in the rate of recovery is proportional to the level of stimulation, further demonstrating that the impairment of Ca2+ homeostasis in the aged neurones appears only during excessive stimulation but not in resting conditions. Simultaneous assessment of the [Ca2+]i and mitochondrial status indicate that the changes in Ca2+ homeostasis are secondary to age-dependent changes in mitochondrial function. In the aged neurones, the mitochondria show a small, chronic depolarisation and also a delay in repolarization following the stimulus-evoked mitochondrial depolarization. Whereas the mitochondrial depolarization can be seen as an adaptive mechanism that can reduce the free radicals production, it also imposes metabolic constraints on the system. As a result, the aged neurones become relatively more dependent on the glycolytic ATP production. The present results show that the changes in Ca2+ homeostasis associated with ageing are mainly due to a metabolic dysfunction in which the mitochondrial impairment plays an important role.

[1] Xiong, J., A. Verkhratsky and E. C. Toescu (2002). J.Neurosci 22(24): 10761-10771.

Keywords (Optional):