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(American Journal of Pathology. 1998;153:447-456.)
© 1998 American Society for Investigative Pathology

Regular Articles

Apoptosis of Retrogradely Degenerating Neurons Occurs in Association with the Accumulation of Perikaryal Mitochondria and Oxidative Damage to the Nucleus

Nael A. Al-Abdulla* and Lee J. Martin*

From the Department of Pathology,* Division of Neuropathology, and Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland

The mechanisms for neuronal apoptosis after axotomy and target deprivation in the adult central nervous system are poorly understood. We used a unilateral occipital cortex ablation model in the adult rat to test the hypothesis that apoptotic retrograde neurodegeneration in the dorsal lateral geniculate nucleus occurs in association with oxidative stress and mitochondrial abnormalities. Immunodetection of 8-hydroxy-2'-deoxyguanosine, a marker for oxidative injury to DNA, demonstrated that these apoptotic neurons undergo oxidative stress. Dual immunolabeling for the retrograde tracer Fluorogold to identify projection neurons and for 8-hydroxy-2'-deoxyguanosine demonstrated that apoptotic, oxidatively damaged neurons are geniculocortical projection neurons. By electron microscopy, degeneration of dorsal lateral geniculate nucleus neurons evolved in association with a transient increase in mitochondria within the perikaryon of dying neurons during the transition between chromatolysis and early apoptosis. The morphological integrity of mitochondria was preserved until late in the progression of apoptosis. The dorsal lateral geniculate nucleus ipsilateral to the cortical lesion had a transient increase in cytochrome c oxidase activity, and geniculocortical neurons at the transitional, early apoptotic stage accumulated cytochrome c oxidase activity. We conclude that axotomy-induced, retrograde neuronal apoptosis in the adult central nervous system occurs in association with the accumulation of functionally active mitochondria within the perikaryon and oxidative damage to nuclear DNA.

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