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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    • "Furthermore, they may also differ in respect to their motor phenotypes, which include severe and early onset of motor, gait, balance and behavioral disturbances, and the neuropathological features [139]. The highlighted cognitive behavioral, motor, and neuropathological heterogeneity of the transgenic tau animal models make them difficult to use in AD translational research, and much attention also needs to be paid in selecting an all-encompassing tau model to investigate the properties of novel drugs for treatment or neuroradiological tracers to diagnose AD [2] [140] [141]. Variables such as the strain, age, and expression level of the transgene and gender of animal models influence the disease progression and its pathophysiology , thereby confounding the results of studies seeking to discover novel biomarkers and therapies for AD. "
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    ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
    Journal of Alzheimer's disease: JAD 09/2015; 47(4):815-843. DOI:10.3233/JAD-150136 · 4.15 Impact Factor
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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]. "

    Current Alzheimer Research 08/2014; 11(7):623-5. DOI:10.2174/156720501107140815102453 · 3.89 Impact Factor
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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.
    PLoS ONE 06/2014; 9(6):e100760. DOI:10.1371/journal.pone.0100760 · 3.23 Impact Factor
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