Blocking A 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 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: 6.34). 12/2008; 28(47):12163-75. DOI: 10.1523/JNEUROSCI.2464-08.2008
Source: PubMed


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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    • "Furthermore, intracerebral injection of Aβ to mutant tau transgenic mice was reported to cause elevated tau phosphorylation [28]. Consistently, inhibition of Aβ accumulation markedly reduces the onset of tau pathology [29]. In the present study, we found that tau phosphorylation markedly decreased after FLZ treatment, which might at least partially be attributed to FLZ’s inhibitory effect on Aβ. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ's neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ's inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β.
    PLoS ONE 11/2013; 8(11):e78033. DOI:10.1371/journal.pone.0078033 · 3.23 Impact Factor
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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 · 6.34 Impact Factor
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