Targeting Phospho-Ser422 by Active Tau Immunotherapy in the THYTau22 Mouse Model: A Suitable Therapeutic Approach

Alzheimer&Tauopathies, Centre de Recherches Jean-Pierre Aubert, Lille, France.
Current Alzheimer research (Impact Factor: 3.89). 01/2012; 9(4):397-405. DOI: 10.2174/156720512800492503
Source: PubMed


Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.

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    • "Due to the central role of NFTs in dementia, immunotherapy targeting these tau proteinous aggregates is an important area of research [13] [14]. Notably, an active immunotherapy targeting the tau pathological epitope phospho- Ser422 was found to be efficient, resulting in tau clearance and improved cognitive deficits promoted by tau pathology in a well-defined tau transgenic model [15]. Like A oligomers , the putative role of tau oligomers in AD pathophysiology has prompted an investigation into tau oligomers as potential immunotherapeutic targets for AD and tauopathies [16]. "

    Full-text · Article · Aug 2014 · Current Alzheimer Research
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    • "Tau amounts were determined after different dilutions using the INNOTEST hTau Ag (Fujirebio/Innogenetics, Belgium) that is a sandwich ELISA microplate assay for the quantitative determination of human Tau antigen in fluids. Capture antibody is the AT120 antibody and biotinylated antibodies HT7 and BT2 are detecting antibodies [39], [40]. To allow for comparisons among the three fractions, dilution factors were included to compare final concentrations in a volume dependent manner. "
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    ABSTRACT: Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Targeting specific phospho-tau sites through passive immunization may be useful to slow, or even reverse, the progression of a disease. Antibody uptake resulted in reduced tau phosphorylation , and clearance of pathological tau protein in brain slices up to significantly improved cognitive performance in Thy-Tau22 transgenic mice (Troquier et al., 2012; Gu et al., 2013b). However, repeated immunization of mice with phospho-tau peptides may cause neuroinflammation (Rozenstein-Tsalkovich et al., 2013). "
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    ABSTRACT: Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.
    Full-text · Article · May 2014 · Frontiers in Molecular Neuroscience
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