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

JULIA LESCHIK; ALFRED WELZEL; CARINA WEISSMANN; ANNE ECKERT; ROLAND BRANDT

JOURNAL OF NEUROCHEMISTRY

Wiley Interscience

Año: 2007 vol. 101 p. 1303 - 1315

0022-3042

Alzheimer’s disease (AD) is characterized by massive neuron loss in distinct brain regions, extracellular accumulations of the amyloid precursor protein-fragment amyloid-b (Ab) and intracellular tau fibrils containing hyperphosphorylated tau. Experimental evidence suggests a relation between presenilin (PS) mutations, Ab formation, and tau phosphorylation in triggering cell death; however, how Ab and PS affect taudependent 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, Ab amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Ab inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b (Ab) and intracellular tau fibrils containing hyperphosphorylated tau. Experimental evidence suggests a relation between presenilin (PS) mutations, Ab formation, and tau phosphorylation in triggering cell death; however, how Ab and PS affect taudependent 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, Ab amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Ab inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b formation, and tau phosphorylation in triggering cell death; however, how Ab and PS affect taudependent 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, Ab amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Ab inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b and PS affect taudependent 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, Ab amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Ab inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b amplified degeneration in the presence of wt tau but not of PHP tau. The data indicate that PS1 and Ab inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b inversely modulate tau-dependent neurodegeneration at distinct steps. They indicate that the mode by which PHP tau causes neurotoxicity is downstream of Ab and that tau phosphorylation is the limiting factor in Ab-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.b and that tau phosphorylation is the limiting factor in Ab-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.b-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. Keywords: Alzheimer’s disease, amyloid precursor protein/ Ab, herpes simplex virus, presenilin, tau, transgenic cortical cultures.Alzheimer’s disease, amyloid precursor protein/ Ab, herpes simplex virus, presenilin, tau, transgenic cortical cultures.b, herpes simplex virus, presenilin, tau, transgenic cortical cultures. J. Neurochem. (2007) 101, 1303–1315.(2007) 101, 1303–1315.