Different tau epitopes define Aβ42-mediated tau insolubility

Alzheimer's disease (AD) is characterized by extracellular beta-ainyloid (A beta(42))-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks Using human SH-SY5Y neuroblastoma cells overexpressing wild-type and Mutant forms of human tau. Exposure to pre-aggregated forms of A beta(42) caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the A beta(42)-mediated decrease in tau Solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope. (c) 2005 Elsevier Inc. All rights reserved.