Pathological Stages of Abnormally Processed Tau Protein During Its Aggregation into Fibrillary Structures in Alzheimer’s Disease

Abstract

Abnormal aggregation of tau protein within the cytoplasm of susceptible neurons has been considered one of the major hallmarks that define the neuropathology of Alzheimer’s disease (AD) (Iqbal et al., 2010; Pritchard et al., 2011). At early stages of neuronal degeneration tau protein is accumulated in the form of early non-assembled aggregates that may alter the normal functioning of affected neurons (Hoozemans et al., 2009; Luna-Munoz et al., 2007). Nonfibrillar aggregation of tau protein as a pre-tangle state has been reported to occur early in the disease but also observed in nondemented very old individuals (Garcia-Sierra et al., 2000). Some studies have reported that oligomeric species of tau protein represent the toxic structures rather than fibrillary structures (Berger et al., 2007; Maeda et al., 2006), however few studies have analyzed and determined a positive correlation between the load of pre-tangle carrying neurons and the clinical symptoms of AD. Further alterations in neurons may occur when the soluble aggregates of tau become assembled into insoluble polymers referred to as paired helical filaments (PHFs) that may also obstruct the transit and distribution of intracellular components, modify the neuronal morphology and alter the cytoskeleton (Ballatore, Lee & Trojanowski, 2007; Kidd, 2006). These filaments progressively coalesce into neurofibrillary tangles (NFTs) which eventually lead to the neuronal death (Guo & Lee, 2011). It is generally accepted that in AD cases, the density of NFTs is the best correlate with the dementia score (Arriagada, Marzloff & Hyman, 1992; Gomez-Isla et al., 1997).