Neuropil threads of Alzheimer's disease show a marked alteration of the normal cytoskeleton

Abstract

Abnormal neurites, neuropil threads, are a widespread and characteristic lesion of Alzheimer's disease likely to play a major role in the cognitive impairment of this disease. Contrary to normal neurites, neuropil threads contain straight and paired helical filaments that contain the microtubule-associated protein tau and ubiquitin. It is not known whether these abnormal filaments are added to or replace the normal cytoskeleton. In this study, we examined the fine structure of neuropil threads and carried out a morphometric analysis of the neurofilaments and abnormal filaments contained in the neuropil threads by using an antiserum to tau and colloidal gold immuno-electron microscopy. Almost 70% of the neuropil threads contained straight or paired helical filaments with no neurofilaments. The total number of filaments in each neuropil thread remained essentially unchanged either when straight or paired helical filaments were present alone or when they coexisted either together or with neurofilaments. When the three types of filaments were expressed as a proportion of the total, a linear inverse correlation was found between neurofilaments and straight filaments as well as between straight and paired helical filaments. Approximately 10% of the neuropil threads were found to be myelinated axons. It is concluded that straight filaments are likely to replace neurofilaments, that they in turn might be replaced by paired helical filaments, and that this process occurs in axons as well as dendrites.

Mitochondrial Abnormalities in Alzheimer's Disease

“…To identif y the pathology of AD, we used antisera to (Perry et al, 1991) to show N F T and a monoclonal antibody (4G8) to A␤ (K im et al, 1988) for senile plaques. Nucleic acid and protein oxidative damage was respectively identified with antibodies to 8-hydroxyguanosine (8-OHG; Trevigen) and nitrotyrosine (clone 7A2; gift from J. S. Beckman, University of Alabama, Birmingham, AL).…”

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…These factors may then initiate a cascade of events leading to plaque/tangle generation and neurodegeneration. These include the appearance of apoptotic and mitotic markers in "pre-tangle" neurons [155][156][157] and the activation of developmentassociated signal transduction pathways resulting in aberrant cellular changes normally associated with development, such as neuropil thread formation [17,19,241,242]. Tau kinases such as CDK5, GSK3β and Mark1 normally play critical roles in cell cycle control, establishment of neuronal polarity and axonal outgrowth [243][244][245][246], so their roles in tau toxicity may therefore be due to aberrant activation of these same functions during the course of AD pathogenesis [147,[247][248][249] 3b Dendritic tau accumulation leads to tau secretion via multiple mechanisms…”

Reactive Oxygen Species Mediate Cellular Damage in Alzheimer Disease

“…Insolubility has been linked to the most well known posttranslational change of τ-abnormal phosphorylation (27,31) and a number of specific kinases and phosphates have been implicated (reviewed in (119)). However, while increased phosphorylation decreases microtubule stability, a salient feature of the pathology of Alzheimer disease (1,2,43,73,75,76), NFT insolubility is not mediated by phosphorylation (108). Indeed, in vitro phosphorylation of normal τ or complete dephosphorylation of NFT has no effect on their solubility (27,31,33,108).…”