Tt. Rohn et al., Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease, AM J PATH, 158(1), 2001, pp. 189-198
Citations number
49
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
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.