Different tau epitopes define Aβ42-mediated tau insolubility

Division of Psychiatry Research, University of Zürich, August Forel Street 1, 8008 Zürich, Switzerland.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 01/2006; 337(4):1097-101. DOI: 10.1016/j.bbrc.2005.09.168
Source: PubMed


Alzheimer's disease (AD) is characterized by extracellular beta-amyloid (Abeta(42))-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks using human SH-SY5Y neuroblastoma cells overexpressing wild-type and mutant forms of human tau. Exposure to pre-aggregated forms of Abeta(42) caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the Abeta(42)-mediated decrease in tau solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope.

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    • "PHF1 IHC produced inconsistent results in our hands. Therefore, the main experiments reported here were based on IHC for pS422, an epitope known to become phosphorylated in neurodegenerative tauopathies (Bussiere et al., 1999; Collin et al., 2014; Pennanen and Gotz, 2005; Guillozet-Bongaarts et al., 2006). Whole mount retinas were taken for dual-label immunofluorescence using general methods published from our group (Koliatsos et al., 2011; Xu et al., 2009 ). "
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    ABSTRACT: Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Experimental Neurology
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    • "We raised an antibody to the S422 phosphorylation site in tau, a disease-specific phospho-epitope that is associated with tau misfolding (Bussiere et al., 1999; Pennanen and Gö tz, 2005; Guillozet-Bongaarts et al., 2006). Tau/pS422 is prominent in early stages of Alzheimer's disease and persists until late-stage disease, making it an attractive target for antibody therapeutics (Guillozet-Bongaarts et al., 2006; Vana et al., 2011). "
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    ABSTRACT: The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] /* */
    Preview · Article · Jul 2014 · Brain
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    • "To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology (Pennanen and Gotz, 2005). The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. "
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    ABSTRACT: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are complex human brain disorders that affect an increasing number of people worldwide. With the identification first of the proteins that aggregate in AD and FTLD brains and subsequently of pathogenic gene mutations that cause their formation in the familial cases, the foundation was laid for the generation of animal models. These recapitulate essential aspects of the human conditions; expression of mutant forms of the amyloid-β protein-encoding APP gene in mice reproduces amyloid-β (Aβ) plaque formation in AD, while that of mutant forms of the tau-encoding microtubule-associated protein tau (MAPT) gene reproduces tau-containing neurofibrillary tangle formation, a lesion that is also prevalent in FTLD-Tau. The mouse models have been complemented by those in lower species such as C. elegans or Drosophila, highlighting the crucial role for Aβ and tau in human neurodegenerative disease. In this review, we will introduce selected AD/FTLD models and discuss how they were instrumental, by identifying deregulated mRNAs, miRNAs and proteins, in dissecting pathogenic mechanisms in neurodegenerative disease. We will discuss some recent examples, which includes miRNA species that are specifically deregulated by Aβ, mitochondrial proteins that are targets of both Aβ and tau, and the nuclear splicing factor SFPQ that accumulates in the cytoplasm in a tau-dependent manner. These examples illustrate how a functional genomics approach followed by a careful validation in experimental models and human tissue leads to a deeper understanding of the pathogenesis of AD and FTLD and ultimately, may help in finding a cure.
    Preview · Article · Aug 2012 · Frontiers in Physiology
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