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

被引:50
作者
Leschik, Julia
Welzel, Alfred
Weissmann, Carina
Eckert, Anne
Brandt, Roland
机构
[1] Univ Osnabruck, Dept Neurobiol, D-49076 Osnabruck, Germany
[2] Univ Basel, Psychiat Clin, Neurobiol Res Lab, Basel, Switzerland
关键词
Alzheimer's disease; amyloid precursor protein/A beta; herpes simplex virus; presenilin; tau; transgenic cortical cultures;
D O I
10.1111/j.1471-4159.2006.04435.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer's disease (AD) is characterized by massive neuron loss in distinct brain regions, extracellular accumulations of the amyloid precursor protein-fragment amyloid-beta (A beta) and intracellular tau fibrils containing hyperphosphorylated tau. Experimental evidence suggests a relation between presenilin (PS) mutations, A beta formation, and tau phosphorylation in triggering cell death; however, how A beta 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, A beta amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and A beta inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of A beta and that tau phosphorylation is the limiting factor in A beta-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.
引用
收藏
页码:1303 / 1315
页数:13
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