Inverse and distinct modulation of tau-dependent neurodegeneration by presenilin 1 and amyloid-β in cultured cortical neurons: Evidence that tau phosphorylation is the limiting factor in amyloid-β-induced cell death

Abstract

Alzheimer's disease (AD) is characterized by massive neuron loss in distinct brain regions, extracellular accumulations of the amyloid precursor protein-fragment amyloid-β (Aβ) and intracellular tau fibrils containing hyperphosphorylated tau. Experimental evidence suggests a relation between presenilin (PS) mutations, Aβ formation, and tau phosphorylation in triggering cell death; however, how Aβ and PS affect tau-dependent degeneration is unknown. Using herpes simplex virus 1-mediated gene-transfer of fluorescent-tagged tau constructs in primary cortical neurons, we demonstrate that tau expression exerts a neurotoxic effect that is increased with a construct mimicking disease-like hyperphosphorylation [pseudohyperphosphorylated (PHP) tau]. Live imaging revealed that PHP tau expression is associated with increased perikarya suggesting the development of a 'ballooned' phenotype as a specific feature of tau-mediated cell death. Transgenic expression of PS1 suppressed tau-induced neurodegeneration. In contrast, Aβ amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Aβ inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Aβ and that tau phosphorylation is the limiting factor in Aβ-induced cell death. Suppression of tau expression or inhibition of tau phosphorylation at disease-relevant sites may provide an effective therapeutic strategy to prevent neurodegeneration in Alzheimer's disease. © 2007 The Authors.