Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines.
Aggregation of amyloid-beta (Abeta) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Abeta-cascade hypothesis, Abeta is considered toxic for neurons and Tau a downstream target of Abeta. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Abeta 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 Ca(2+), 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 GSK3beta, 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 Abeta-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Abeta-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca(2+) levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Abeta oligomers can be evoked by cell stressors (e.g., H(2)O(2), glutamate, serum deprivation), suggesting some common mechanism of signaling.
Zempel
Hans
H
Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
Thies
Edda
E
Mandelkow
Eckhard
E
Mandelkow
Eva-Maria
EM
D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites; D049229:Dendritic Spines; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016900:Neurofilament Proteins; D010446:Peptide Fragments; D016875:tau Proteins; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases; D002118:Calcium
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