Topographic associations between DNA fragmentation and Alzheimer's disease neuropathology in the hippocampus

To identify whether the process of apoptosis bears a topographic relationship to selected aspects of Alzheimer's disease (AD) pathology, we used an in situ nick translation method (TUNEL) to map DNA fragmentation in hippocampal sections immunostained for abnormally phosphorylated tau, which exists in the neurofibrillary tangles (NFTs) and in the dystrophic neurites associated with senile plaques. To ascertain associations of DNA fragmentation with glia, TUNEL was combined with immunohistochemistry for the astrocyte marker, glial fibrillary acidic protein (GFAP), or the microglial antigen OX-42. Consistent with previous reports, the incidence of putative DNA fragmentation detected by TUNEL was much higher in the AD brain, compared to non-demented subjects. While most TUNEL-positive cells did not exhibit any systematic topographic relationship to senile plaques, which were visualized by immunostain of abnormally phosphorylated tau for dystrophic neurites, DNA fragmentation was found frequently within cells containing NFTs. In hippocampal sections prepared to visualize glia, DNA fragmentation was not observed in GFAP-positive astrocytes, but some OX-42-positive microglia exhibited TUNEL signals. Other TUNEL-positive cells were found frequently in proximity to glia. The data suggest that cells compromised by the deposition of NFTs are prone to initiate the process of apoptosis. Furthermore, some glial populations appear to be apoptotic in the AD brain.