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
- 9 January 2007
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 101 (5), 1303-1315
- https://doi.org/10.1111/j.1471-4159.2006.04435.x
Abstract
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.Keywords
This publication has 58 references indexed in Scilit:
- Tau Aggregation and Progressive Neuronal Degeneration in the Absence of Changes in Spine Density and Morphology after Targeted Expression of Alzheimer's Disease-Relevant Tau Constructs in Organotypic Hippocampal SlicesJournal of Neuroscience, 2006
- A γ-Secretase-independent Mechanism of Signal Transduction by the Amyloid Precursor ProteinJournal of Biological Chemistry, 2005
- The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced NeurodegenerationJournal of Neuroscience, 2005
- Pathways towards and away from Alzheimer's diseaseNature, 2004
- Tau alteration and neuronal degeneration in tauopathies: mechanisms and modelsBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2004
- PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutationsThe EMBO Journal, 2004
- Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the β-amyloid peptide intracellularly in hippocampal and cortical neuronsNeuroscience, 2004
- Direct interaction of soluble human recombinant tau protein with Aβ 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase IIFEBS Letters, 2002
- Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau proteinBiochemical Journal, 2001
- Amino-terminal region of the β-amyloid precursor protein activates mitogen-activated protein kinaseNeuroscience Letters, 1995