Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging

Morphological and biochemical alterations have been described in neurons of the aged human brain. However, the cell death process associated with neuronal senescence remains to be elucidated. Apoptosis and autophagic degeneration, two modes of programmed cell death described in embryogenesis and tissue renewal in adult, have been observed in nigral dopaminergic neurons in patients with Parkinson's disease. In the present study, we made the hypothesis that programmed cell death may be also involved in the death of nigral dopaminergic neurons occurring during aging. Cell death types were defined by morphological criteria identified at subcellular level. We thus performed an ultrastructural analysis in order to search for apoptotic and autophagic features in melanized neurons of the substantia nigra in four normal aged subjects. Morphological characteristics of apoptosis, such as contact loss with surrounding tissues, cell shrinkage and chromatin condensation, were found in 2% of the total number of melanized neurons analyzed. Although endoplasmic reticulum appeared normal, mitochondria were markedly shrunken. Fragments of melanized neurons were found in glial cells. Autophagic degeneration or necrosis were not detected in melanized neurons. Signs of oxidative stress, such as vacuolation of mitochondria, were observed in melanized neurons devoid of apoptotic features. These findings demonstrate that apoptosis is involved in cell death of nigral dopaminergic neurons during normal aging. Since morphological abnormalities found in this study, such as marked mitochondrial shrinkage in apoptotic neurons, were not observed in patients with Parkinson's disease, the mechanisms underlying apoptosis may be different in aging and pathology.