We present the first evidence for carbonyl‐related posttranslational modifications of neurofilaments in the neurofibrillary pathology of Alzheimer's disease (AD). Two distinct monoclonal antibodies that consistently labeled neurofibrillary tangles (NFTs), neuropil threads, and granulovacuolar degeneration in sections of AD tissue also labeled the neurofilaments within axons of the white matter following modification by reducing sugars, glutaraldehyde, formaldehyde, or malondialdehyde. The epitope recognized by these two antibodies shows a strict dependency for carbonyl modification of the neurofilament heavy subunit. The in vivo occurrence of this neurofilament modification in the neurofibrillary pathology of AD suggests that carbonyl modification is associated with a generalized cytoskeletal abnormality that may be critical in the pathogenesis of neurofibrillary pathology. Furthermore, the data presented here support the idea that extensive posttranslational modifications, including oxidative stress‐type mechanisms, through the formation of cross‐links, might account for the biochemical properties of NFTs and their resistance to degradation in vivo.
In this study, the direct comparison of biopsy and autopsy tissue by morphological and immunocytochemical techniques, respectively, was used to document cytoskeletal changes of dystrophic neurites (DN) of senile plaques in Alzheimer's disease. This dual approach demonstrated several unreported abnormalities which, together with analogous findings in several experimental models, suggest that DN are associated with deficiencies in fast axonal transport and replacement of the cytoskeleton by an array of related abnormal filaments.
The simultaneous presence of intracellular neurofibrillary tangles (NFT) and extracellular senile plaques in Alzheimer's disease (AD) suggests that the two lesions could be synergistically interrelated. However, although the main protein components of NFT and senile plaques, tau (tau) and amyloid beta-protein, respectively, are well characterized, the molecular mechanisms responsible for their deposition in lesions are unknown. We demonstrate, using four independent techniques, that tau directly interacts with a conformation-dependent domain of the amyloid beta-protein precursor (beta PP) encompassing residues beta PP714-723. The putative tau-binding domain includes beta PP717 mutation sites that are associated with familial forms of AD. Our findings strongly suggest that NFT and senile plaques, often thought of as independent structures, may play a role in each other's formation during the pathogenesis of AD.
This study presents evidence for plasma membrane abnormalities of the dystrophic neurites in senile plaques of Alzheimer's disease. We found that the plasma membranes of dystrophic neurites are more labile to fixation than those membranes of other cells of the senile plaque or of normal neurites distant from senile plaques. Further, we found vesicles in the extracellular space adjacent to dystrophic neurites and similar to those within them, suggesting that the increased lability seen in our preparations may, in vivo, be associated with release of neuritic contents. Plasma membrane alterations may be critical to deposition of amyloid-beta in senile plaques from the abundant beta-protein precursor of dystrophic neurites. The consequences of altered membrane integrity, such as calcium influx, lipid peroxidation and free radical damage, could also be responsible for many of the pathological correlates of the disease.
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