Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem

Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 06/2011; 118(4):658-67. DOI: 10.1111/j.1471-4159.2011.07337.x
Source: PubMed


Targeting hyperphosphorylated tau by immunotherapy is emerging as a promising approach to treat tauopathies such as Alzheimer's disease and frontotemporal dementia. We have previously reported that active tau immunization clears tau aggregates from the brain and attenuates or prevents functional impairments in two different tangle mouse models. Here, we assessed the efficacy of passive immunization with the PHF1 antibody, which targets a phospho-epitope within one of our active immunogens. Homozygous female tangle mice (JNPL3, 2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 μg/125 μL; n = 10 per group) for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue was subsequently harvested for analyses of treatment efficacy. The treated mice performed better than controls on the traverse beam task (p < 0.03), and had 58% less tau pathology in the dentate gyrus of the hippocampus (p = 0.02). As assessed by western blots, the antibody therapy reduced the levels of insoluble pathological tau by 14-27% (PHF1, p < 0.05; PHF1/total tau, p < 0.0001) and 34-45% (CP13 or CP13/total tau, p < 0.05). Levels of soluble tau and sarkosyl soluble tau were unchanged, compared with controls, as well as total tau levels in all the fractions. Plasma levels of PHF1 correlated inversely with tau pathology in the brainstem (p < 0.01), with a strong trend in the motor cortex (p < 0.06) as well as with insoluble total tau levels (p < 0.02), indicating that higher dose of antibodies may have a greater therapeutic effect. Significant correlation was also observed between performance on the traverse beam task and PHF1 immunoreactivity in the dentate gyrus (p < 0.05) as well as with insoluble PHF1/total tau ratio on western blots (p < 0.04). These results show that passive immunization with tau antibodies can decrease tau pathology and functional impairments in the JNPL3 model. Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models in which thorough cognitive assessment can be performed.

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    • "or the World Health Organization's clinical trial registry. In the first program to demonstrate the efficacy of tau-based immunotherapy, this approach has been tested by injecting anti-phospho-tau antibody PHF1, which recognizes the pS396/pS404 epitope, intraperitoneally to JNPL3 (P301L) tau transgenic mice, with preliminary findings indicating that treated animals showed decreased tau pathology and functional impairment[94]. Similar effects were obtained also with other antibodies against the pS396/pS404 epitope[95,96]. A new class of monoclonal antibodies could behave as chaperones protecting targeted proteins against conformational changes[97], and may effectively inhibit aggregation and toxicity of misfolded proteins[98]. "
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    ABSTRACT: Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer's disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT(+)). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway.
    Full-text · Article · Jan 2016 · Expert Review of Neurotherapeutics
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    • "However, there was no change in survival between mice injected with either PHF1 or MC1 from 6 to 14 months of age versus control Tg mice (d'Abramo et al., 2013). Previously, it had been shown that PHF1 is able to decrease tau-related pathology when treatment is started prior to the onset of disease (Boutajangout et al., 2011). Together, these results suggest that, although immunotherapy directed toward tau holds promise , there is some risk of toxicity. "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Neuron
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    • "Given that tau is an intracellular protein, immunotherapy would seem to have little chance of success: antibodies have to traverse not only the blood–brain barrier but also the neuronal plasma membrane. Nevertheless, many groups have shown that immunotherapy in tau transgenic mice leads to reduced pathology (Boutajangout et al., 2011; Chai et al., 2011; d&apos;Abramo et al., 2013; Yanamandra et al., 2013; Castillo-Carranza et al., 2014). One explanation for these findings is that antibodies inhibit transcellular spreading of tau aggregates (Clavaguera et al., 2009; Voss et al., 2012). "
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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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