Inverse and distinct modulation of tau-dependent neurodegeneration by presenilin 1 and amyloid-beta in cultured cortical neurons: evidence that tau phosphorylation is the limiting factor in amyloid-beta-induced cell death
Autor(en): | Leschik, Julia Welzel, Alfred Weissmann, Carina Eckert, Anne Brandt, Roland |
Stichwörter: | ACTIVATED PROTEIN-KINASE; Alzheimer's disease; ALZHEIMERS-DISEASE; amyloid precursor protein/A beta; APOPTOSIS; BALLOONED NEURONS; Biochemistry & Molecular Biology; BRAIN; DNA FRAGMENTATION; herpes simplex virus; HIPPOCAMPAL-NEURONS; Neurosciences; Neurosciences & Neurology; PATHOLOGY; PRECURSOR PROTEIN; presenilin; tau; transgenic cortical cultures; TRANSGENIC MICE | Erscheinungsdatum: | 2007 | Herausgeber: | WILEY | Journal: | JOURNAL OF NEUROCHEMISTRY | Volumen: | 101 | Ausgabe: | 5 | Startseite: | 1303 | Seitenende: | 1315 | Zusammenfassung: | 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. |
ISSN: | 00223042 | DOI: | 10.1111/j.1471-4159.2006.04435.x |
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geprüft am 20.05.2024