Article

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

Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2010; 30(36):11938-50. DOI: 10.1523/JNEUROSCI.2357-10.2010
Source: PubMed

ABSTRACT

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.

    • "These results are similar to those previously reported by us and other authors [4] [5] [6] [7]. However, Zempel et al. [10] showed recently that DMEM-F12 medium alone induces small [Ca 2+ ] cyt increases as well, "
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    ABSTRACT: Oligomers of the amyloid β peptide (Aβo) are becoming the most likely neurotoxin in Alzheimeŕs disease. Controversy remains on the mechanisms involved in neurotoxicity induced by Aβo and the targets involved. We have reported that Aβo promote Ca(2+) entry, mitochondrial Ca(2+) overload and apoptosis in cultured cerebellar neurons. However, recent evidence suggests that some of these effects could be induced by glutamate receptor agonists solved in F12, the media in which Aβo are prepared. Here we have tested the effects of different media on Aβo formation and on cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in rat cerebellar and hippocampal cell cultures. We found that Aβo prepared according to previous protocols but solved in alternative media including saline, MEM and DMEM do not allow oligomer formation and fail to increase [Ca(2+)]cyt. Changes in the oligomerization protocol and supplementation of media with selected salts reported to favor oligomer formation enable Aβo formation. Aβo prepared by the new procedure and containing small molecular weight oligomers increased [Ca(2+)]cyt, promoted mitochondrial Ca(2+) overload and cell death in cerebellar granule cells and hippocampal neurons. These results foster a role for Ca(2+) entry in neurotoxicity induced by Aβo and provide a reliable procedure for investigating the Ca(2+) entry pathway promoted by Aβo.
    No preview · Article · Dec 2015 · Neuroscience Letters
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    • "In addition to its buildup within neurons, more recent studies demonstrated that tau is also released in the extracellular space (Gómez-Ramos et al., 2006; Avila, 2010); and that increased levels of tau (total and phosphorylated) in the human's cerebrospinal fluid (CSF) are associated with an increased risk of developing AD (Blennow et al., 2010). Tau protein is traditionally considered to be localized in axons; however, when neurons are exposed to Aβ oligomers, tau relocates to somatodendritic compartments in association with loss of spines and microtubule breakdown (Zempel et al., 2010). More recent data demonstrated the presence of tau at synapses in physiologic and pathological conditions (Pooler et al., 2014). "

    Full-text · Dataset · Nov 2015
    • "Taucanbephosphorylatedbyseveralkinasesthatare overactiveinADbrains(e.g.,GSK-3β,Cdk5,Cdc2,PKR,JNK andotherMAPKs;reviewedbyMandelkowandMandelkow, 2012).SignificantevidencesuggeststhatAβO-mediatedtau phosphorylationleadstocytoskeletondisruptionandsynaptic loss(Zempeletal.,2010,2013;ZempelandMandelkow,2012). ZempelandcollaboratorshaveshownthatAβOsinducetaumissorting ,aphenomenoninwhichaxonaltaumovestodendritesin hyperphosphorylatedform,disruptingcytoskeletalorganization andaxonaltransport(Zempeletal.,2010),ultimatelyinstigating neuronalcollapse.Inaccordwiththisnotion,AβOswereshown toimpairactivity-dependenttaure-localizationinneurons (Frandemicheetal.,2014). "
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    ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-b peptide (Ab) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Ab leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Ab oligomers (AbOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Ab oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.
    No preview · Article · May 2015 · Frontiers in Cellular Neuroscience
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