The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition

The structural changes of Alzheimer's disease (AD) include a widespread alteration of neuronal cell processes in addition to senile plaques and neurofibrillary tangles. Since the antigenic characteristics of these abnormal neurites are similar to those of the abnormal neurites associated with the senile plaques, the question has been raised as to whether the widespread neuritic alteration is secondary to the deposition of amyloid. To answer this question, we examined brains from 2 subjects with a longer‐lasting form of subacute sclerosing panencephalitis (SSPE) characterized by the presence of numerous neurofibrillary tangles but no senile plaques, 3 subjects with AD, and 2 age‐matched controls. Light and electron immunocytochemical analyses revealed that abnormal neurites are present diffusely in SSPE cerebral cortex in the absence of amyloid deposits. These abnormal neurites were qualitatively identical to the widespread abnormal neurites of AD. The abnormal neurites, in contrast to the neurites of control brains, immunoreacted with antibodies to tau and ubiquitin. These distinctive antigenic features were due to the presence in these abnormal neurites of straight filaments, 14 to 16 nm in diameter, mixed with a few paired helical filaments. The spatial distribution of the widespread neuritic alteration correlated with that of neurofibrillary tangles in both conditions, but not with that senile plaques in AD. The present findings demonstrate that a diffuse alteration of neurites similar to that present in AD takes place independently of the deposition of amyloid in SSPE, and they are consistent with the hypothesis that in AD, also, this alteration is not secondary to the deposition of amyloid. It is suggested that the diffuse abnormality of neurites and the formation of neurofibrillary tangles in AD and SSPE, as well as in other conditions, are the expression of a widespread alteration of the neuronal cytoskeleton that involves the ubiquitin system and is likely to be caused by sustained stress conditions.