Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer's disease.

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.

Plasma membrane fragility in dystrophic neurites in senile plaques of Alzheimer's disease: an index of oxidative stress.

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.

Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease.

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.

Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer's disease.

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.

Characterization of the association of phospholipase C-delta with Alzheimer neurofibrillary tangles.

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. We have previously demonstrated that an antibody to the PLC isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of AD patients [Am. J. Pathol., 139 (1991) 737-742]. To clarify the crucial involvement of abnormal PLC-delta accumulation contributing to the formation of NFT, we performed light and electron microscopic immunocytochemistry. To determine PLC-delta's association with NFT, its resistance to solubilization was also studied. Anti-PLC-delta antibody marked the same NFT-bearing neurons containing tau immunoreactivity with tau more clearly on NFT filaments and PLC-delta covering it superficially at the light microscope level. The double stained preparations with anti-PLC-delta antibody and bFGF binding suggested that PLC-delta is an intracellular marker and is not retained after neuronal death. Employing immunoperoxidase and immunogold electron microscopic immunocytochemistry, we found that the antibody to PLC-delta reacts mostly with amorphous granular materials, and occasionally with some abnormal filaments within NFT. Nevertheless, PLC-delta in NFT was resistant to removal by high salt or ionic detergent, indicating it is an integral NFT component. These results indicate that antigenic determinants unique to PLC-delta are mainly present intraneuronally on the amorphous granular components of NFT as well as the abnormal filaments, suggesting PLC-delta's interactions and possible role in the formation of intraneuronal filamentous inclusions in AD.

Chondroitin sulfate proteoglycans are a common component of neuronal inclusions and astrocytic reaction in neurodegenerative diseases.

Previously, we showed three differentially sulfated forms of chondroitin sulfate proteoglycans (CSPG) associated with senile plaques, astrocytes and neurofibrillary tangles in Alzheimer's disease. Here, monoclonal antibodies were used to demonstrate CSPGs in other neurodegenerative diseases. CSPGs were found associated with inclusions of Parkinson's, diffuse Lewy body, Pick's diseases, and progressive supranuclear palsy. Reacting astrocytes in each of these neurodegenerative diseases and Huntington's disease showed immunoreactivity for CSPG. CSPG distribution in a variety of neurodegenerative diseases suggests that similar mechanisms may be involved in the accumulation of proteoglycans in a number of filamentous inclusions.