Blocking A beta(42) Accumulation Delays the Onset and Progression of Tau Pathology via the C Terminus of Heat Shock Protein70-Interacting Protein: A Mechanistic Link between A beta and Tau Pathology

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 12/2008; 28(47):12163-75. DOI: 10.1523/JNEUROSCI.2464-08.2008
Source: PubMed

ABSTRACT The molecular alterations that induce tau pathology in Alzheimer disease (AD) are not known, particularly whether this is an amyloid-beta (Abeta)-dependent or -independent event. We addressed this issue in the 3xTg-AD mice using both genetic and immunological approaches and show that a selective decrease in Abeta(42) markedly delays the progression of tau pathology. The mechanism underlying this effect involves alterations in the levels of C terminus of heat shock protein70-interacting protein (CHIP) as we show that Abeta accumulation decreases CHIP expression and increases tau levels. We show that the Abeta-induced effects on tau were rescued by restoring CHIP levels. Our findings have profound clinical implications as they indicate that preventing Abeta accumulation will significantly alter AD progression. These data highlight the critical role CHIP plays as a link between Abeta and tau and identify CHIP as a new potential target not only for AD but for other neurodegenerative disorders characterized by tau accumulation.

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    • "Some studies suggest that tau expression is required for A␤-mediated toxicity and behavioral defects [105] [106] [107]. Other studies suggest that A␤ accumulation precedes tau pathology [108] [109] [110] [111]. Tau is a phosphoprotein, which promotes the assembly of tubulin into microtubules and helps to stabilize its structure [112]. "
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    • "Blockage of cdk5 transcription by siRNA or incubation with roscovitine, a selective and specific inhibitor of cdk5 activity, both resulted in a suppression of the 12-15LO-dependent effect on tau phosphorylation at specific epitopes. As data from transgenic mice support the hypothesis that Ab can modify cellular metabolic events leading to phosphorylation-specific changes in tau (Oddo et al., 2008) and considering that 12-15LO can also act as an endogenous modulator of Ab (Chu et al., 2012a,b), it was possible that in our study the effect on tau was secondary to that on Ab. However, based on our findings, we conclude that the effect of 12-15LO on tau phosphorylation is independent from it, because suppression of Ab formation by a selective c-secretase inhibitor did not influence the 12-15LO-dependent tau hyperphosphorylation. "
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    ABSTRACT: 12/15-Lipoxygenase (12/15LO) is a lipid-peroxidizing enzyme widely expressed in the central nervous system where it has been involved in the neurobiology of Alzheimer disease (AD) because it modulates Amyloid beta (Aβ) and APP processing. However, its biological effect on tau protein is unknown. We investigated the effect of 12/15LO on tau levels and metabolism in vivo and in vitro and the mechanism involved by using genetic and pharmacologic approaches. While no significant differences were observed in the levels of total tau for both groups, compared with controls, Tg2576 mice over-expressing 12/15LO had elevated levels of phosphorylated tau at two specific epitopes, Ser 202/Thr 205 and Ser 396. In vitro and in vivo studies show that 12/15LO modulates tau metabolism specifically via the cdk5 kinase pathway. Associated with these changes were biochemical markers of synaptic pathology. Finally, 12/15-LO-dependent alteration of tau metabolism was independent from an effect on Aβ. Our findings reveal a novel pathway by which 12/15LO modulates endogenous tau metabolism making this protein an appealing pharmacologic target for treatment of AD and related tauopathies. This article is protected by copyright. All rights reserved.
    Aging cell 07/2013; 12(6). DOI:10.1111/acel.12136 · 5.94 Impact Factor
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    • "In addition, we found that SC-560 treatment did not change the levels of Cdk5 and PP2A (Fig. 5a). SC-560 treatment ameliorates the spatial learning and memory deficits in 3 3 Tg-AD mice The 3 9 Tg-AD mice develop progressive accumulation of plaques and tangles, which are associated with age-dependent cognitive impairment (Oddo et al. 2008). We next sought to determine whether changes in amyloid and tau pathology correlated with improvement of cognitive deficits following SC-560 treatment. "
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    ABSTRACT: Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β-amyloid (Aβ) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month old triple transgenic AD (3×Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3×Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3×Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.
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