Reducing Endogenous Tau Ameliorates Amyloid -Induced Deficits in an Alzheimer's Disease Mouse Model

Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Science (Impact Factor: 31.48). 06/2007; 316(5825):750-4. DOI: 10.1126/science.1141736
Source: PubMed

ABSTRACT Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.

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Available from: Erik Roberson, Aug 20, 2015
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    • "First, tau-deficient neurons have been shown to be resistant to Aβ-mediated neurotoxicity (Rapoport et al., 2002). Second, genetic deficiency of tau in an AD mouse model improved cognitive function and reduced excitotoxic injury (Roberson et al., 2007; Ittner et al., 2010). Third, Shipton and colleagues recently showed that deficiency of tau protected against Aβ-induced impairment of long-term potentiation in hippocampal slices of wild type mice (Shipton et al., 2011). "
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    ABSTRACT: Neuroinflammation is one of the neuropathological hallmarks of Alzheimer’s disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine) receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1-/- mice. First, Mapt+/+ neurons displayed elevated levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when co-cultured with LPS-treated Cx3cr1-/-microglia, which is rescued in Mapt-/- neurons. Second, a neuronal population positive for phospho-S199 (AT8) tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3) in the LPS-treated Cx3cr1-/- mice. Third, genetic deficiency for tau in Cx3cr1-/- mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1-/- mice. Finally, Cx3cr1-/- mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches towards either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.
    Frontiers in Neuroscience 06/2015; 9:196. DOI:10.3389/fnins.2015.00196 · 3.70 Impact Factor
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    • "The causative role of APP (and its proteolytic derivatives) in AD neuropathology is further supported by studies performed in mouse models of the disease (Duyckaerts et al., 2008; Ghosal et al., 2009; Gotz et al., 2004). Finally, downregulation of the Mapt gene in APP mouse models of AD can rescue the memory loss associated with the disease, suggesting a possible role of tau downstream of APP (Roberson et al., 2007; Santacruz et al., 2005). "
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    ABSTRACT: p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases. Here, we report that the amyloid precursor protein (APP) intracellular domain (AICD), which results from the processing of the APP, regulates translation of p44 through a cap-independent mechanism that requires direct binding to the second internal ribosome entry site (IRES) of the p53 mRNA. We also report that AICD associates with nucleolin, an already known IRES-specific trans-acting factor that binds with p53 IRES elements and regulates translation of p53 isoforms. The potential biological impact of our findings was assessed in a mouse model of Alzheimer's disease. In conclusion, our study reveals a novel aspect of AICD and p53/p44 biology and provides a possible molecular link between APP, p44, and tau. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 06/2015; Accepted Pub.. DOI:10.1016/j.neurobiolaging.2015.06.021 · 4.85 Impact Factor
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    • "Afterwards, it was shown that the presence of tau protein is essential to the amyloid-beta induced neurotoxicity, occurring in AD (Rapoport et al., 2002; Roberson et al., 2007; Ittner et al., 2010). Based on these and other reports, it was suggested that Aβ could initiate the pathological process but the presence of tau is needed for the progression of the process. "
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    ABSTRACT: It is well established that some individuals with normal cognitive capacity have abundant senile plaques in their brains. It has been proposed that those individuals are resilient or have compensation factors to prevent cognitive decline. In this comment, we explore an alternative mechanism through which cognitive capacity is maintained. This mechanism could involve the impairment of alternative neural circuitry. Also, the proportion of molecules such as Aβ or tau protein present in different areas of the brain could be important.
    Frontiers in Neuroscience 04/2015; 9:145. DOI:10.3389/fnins.2015.00145 · 3.70 Impact Factor
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