Journal
JOURNAL OF NEUROSCIENCE
Volume 30, Issue 36, Pages 11938-11950Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2357-10.2010
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Funding
- Deutsche Forschungsgemeinschaft
- Breuer Foundation
- European Union
- Bundesministerium fur Bildung und Forschung (Kompetenznetz Degenerative Demenzen)
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Aggregation of amyloid-beta (A beta) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the A beta-cascade hypothesis, A beta is considered toxic for neurons and Tau a downstream target of A beta. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to A beta oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca2+, and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e. g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e. g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3 beta, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The A beta-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that A beta-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca2+ levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of A beta oligomers can be evoked by cell stressors (e.g., H2O2, glutamate, serum deprivation), suggesting some common mechanism of signaling.
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