Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease

Although evidence suggests that neurofibrillary tangles (NFTs) and neuronal tell loss are prominent features of Alzheimer's disease (AD), the relation ship between the two remains unknown. In the present study, the relationshi p between the activation of apoptotic mechanisms and NFT formation in AD wa s investigated using a caspase-cleavage site-directed antibody to fodrin, a n abundant neuronal cytoskeleton protein. This antibody recognized cleavage products of fodrin after digestion by caspase-3, but did not recognize ful l-length fodrin. Itt vitro analysis of this fodrin caspase-cleavage product (CCP) antibody demonstrates that it is a specific probe for the detection of apoptotic but not necrotic pathways in cultured neurons. To determine wh ether caspases cleave fodrin in vivo, tissue sections from controls and AD were immunostained for fodrin (CCPs). Although no staining was observed in control cases, labeling of neurons was observed in the hippocampus of all A D cases, which increased as a function of disease progression. To determine a possible relationship between caspase activation and NFT formation, doub le-labeling experiments with fodrin CCP and PHF-1 were performed. Co-locali zation of these markers was observed in many neurons, and quantitative anal ysis showed that as the extent of NFT formation increased, there was a sign ificant corresponding increase in fodrin CCP immunolabeling (r = 0.84). Tak en together, these results provide evidence for the activation of apoptotic mechanisms in neurons in the AD brain and suggest that there is an associa tion between NFT formation and the activation of apoptotic pathways in AD.