Tau Protein Is Required for Amyloid beta-Induced Impairment of Hippocampal Long-Term Potentiation

Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 02/2011; 31(5):1688-92. DOI: 10.1523/JNEUROSCI.2610-10.2011
Source: PubMed

ABSTRACT Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder of unknown cause characterized by fibrillar accumulation of the Aß-peptide and aggregates of the microtubule-associated protein tau in a hyperphosphorylated form. Already at preclinical stages, AD is characterized by hypometabolic states which are a good predictor of cognitive decline. Here, we summarize recent evidence derived from the study of hibernating animals that brain hypometabolism can trigger PHF-like hyperphosphorylation of tau. We put forward the concept that particular types of neurons respond to a hypometabolic state with an elevated phosphorylation of tau protein which represents a physiological mechanism involved in regulating synaptic gain. If, in contrast to hibernation, the hypometabolic state is not terminated after a definite time but rather persists and progresses, the elevated phosphorylation of tau protein endures and the protective reaction associated with it might turn into a pathological cascade leading to neurodegeneration.
    Journal of Neural Transmission 12/2014; DOI:10.1007/s00702-014-1342-8 · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The amyloid cascade hypothesis has been the prevailing hypothesis in Alzheimer's Disease research, although the final and most wanted proof i.e. fully successful anti-amyloid clinical trials in patients, is still lacking. This may require a better in depth understanding of the cascade. Particularly, the exact toxic forms of Abeta and Tau, the molecular link between them and their respective contributions to the disease process need to be identified in detail. Although the lack of final proof has raised substantial criticism on the hypothesis per se, accumulating experimental evidence in in vitro models, in vivo models and from biomarkers analysis in patients supports the amyloid cascade and particularly Abeta-induced Tau-pathology, which is the focus of this review. We here discuss available models that recapitulate Abeta-induced Tau-pathology and review some potential underlying mechanisms. The availability and diversity of these models that mimic the amyloid cascade partially or more complete, provide tools to study remaining questions, which are crucial for development of therapeutic strategies for Alzheimer's Disease.
    Molecular Neurodegeneration 11/2014; 9(1):51. DOI:10.1186/1750-1326-9-51 · 5.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-beta peptide (Abeta) oligomers induce synaptic loss in AD. Abeta-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3beta, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Abeta may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Abeta-induced synaptic loss, Abeta synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Abeta. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Abeta. In summary, Abeta-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.
    Molecular Neurodegeneration 11/2014; 9(1):48. DOI:10.1186/1750-1326-9-48 · 5.29 Impact Factor

Elizabeth Tunbridge