Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines

By H. Zempel, E. Thies, E. Mandelkow. Journal of Neuroscience, 2010

656 citations recorded by the source corpus.

Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ 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 GSK3β, 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 Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-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 Aβ oligomers can be evoked by cell stressors (e.g., H2O2, glutamate, serum deprivation), suggesting some common mechanism of signaling.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/40b0a15afe92d0304334cf76c0021bc546fb31a7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. L. Mucke
2. D. Selkoe
3. K. Ashe
4. J. Palop
5. G. Bu
6. D. Holtzman

In Neurology

1. D. Selkoe
2. L. Mucke

In Physiology

1. D. Selkoe
2. L. Mucke
3. K. Ashe
4. J. Palop
5. D. Holtzman
6. David Watson
7. G. Bu
8. P. Reddy

Citations in the corpus

• Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration (2010, background): “A recent report (Zempel et al., 2010) suggests that spines might serve as a site of convergence for amyloid beta and tau.”
• Alzheimer's disease. (2011, background): “Many studies employing supraphysiological concentrations of synthetic Ab peptides in oligomeric form (generally larger than dimers/ trimers) have also provided evidence of tau alteration (Zempel et al. 2010) and various neurotoxic effects.”
• The Many Faces of Tau (2011, background): “Acute exposure of neuronal cultures to Ab led to hyperphosphorylation (De Felice et al., 2008) and mislocalization of tau into dendritic spines (Zempel et al., 2010), which, at least in some dendrites, was associated with spine collapse and dendritic degeneration.”