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


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.

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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). "

    • "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.
    Frontiers in Cellular Neuroscience 05/2015; 9. DOI:10.3389/fncel.2015.00191 · 4.29 Impact Factor
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    • "An important question however remains as to how TAU becomes hyperphosphorylated in the first place. The facts that TAU is a substrate of many of the kinases operating in the pathways modulated by Aí µí»½o (Table 2) or by AD risk factors or genes (Table 1) and that TAU is phosphorylated by neurons challenged with Aí µí»½o or other stresses/conditions [95] [96] [97] [98], provide a mechanistic explanation as to TAU hyperphosphorylation in AD [5] [23] [99] [100]. "
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    ABSTRACT: Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively.
    BioMed Research International 08/2014; 2014:167024. DOI:10.1155/2014/167024 · 2.71 Impact Factor
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