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      Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology

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          Abstract

          A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS ( CASS4), Eph ( EPHA1), Fak ( PTK2B) and Rab3-GEF ( MADD) as Tau toxicity modulators. Of these, the focal adhesion kinase Fak behaved as a strong Tau toxicity suppressor in both the eye and an independent focal adhesion-related wing blister assay. Accordingly, the human Tau and PTK2B proteins biochemically interacted in vitro and PTK2B co-localized with hyperphosphorylated and oligomeric Tau in progressive pathological stages in the brains of AD patients and transgenic Tau mice. These data indicate that PTK2B acts as an early marker and in vivo modulator of Tau toxicity.

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          Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles.

          C W Wittmann, M Wszolek, J Shulman … (2001)
          The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster. Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.
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            Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

            J Chapuis, F. Hansmannel, M Gistelinck … (2013)
            Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
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              Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits.

              Karelle Leroy, Luc Buée, Severine Begard … (2006)
              Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Psychiatry
                Journal ID (iso-abbrev): Mol. Psychiatry
                Title: Molecular Psychiatry
                Publisher: Nature Publishing Group
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date (Print): June 2017
                Publication date (Electronic): 26 April 2016
                Volume: 22
                Issue: 6
                Pages: 874-883
                Affiliations
                [1 ]Institut Pasteur de Lille , Lille, France
                [2 ]INSERM, UMR 1167 , Lille, France
                [3 ]Université de Lille , Lille, France
                [4 ]INSERM, UMR-S 1172, Alzheimer and Tauopathies , Lille, France
                [5 ]Univ.Lille, JPArc , Lille, France
                [6 ]CHRU, Memory Clinic , Lille, France
                [7 ]Institute of Clinical Medicine—Neurology and Department of Neurology, University of Eastern Finland and Kuopio University Hospital , Kuopio, Finland
                [8 ]Institute of Biomedicine, University of Eastern Finland , Kuopio, Finland
                [9 ]Centre Hospitalier Régional Universitaire de Lille , Lille, France
                [10 ]Center for Medical Genetics, Ghent University Hospital , Ghent, Belgium
                Author notes
                [* ]Unité d'Epidémiologie et de Santé Publique—INSERM U 1167, Institut Pasteur de Lille , BP 245, Lille 59019, France. E-mail: pierre.dourlen@ 123456pasteur-lille.fr or jean-charles.lambert@ 123456pasteur-lille.fr or bart.dermaut@ 123456pasteur-lille.fr
                [11]

                These two authors are co-last authors.

                Author information
                http://orcid.org/0000-0001-9088-234X
                Article
                Publisher Item ID: mp201659
                DOI: 10.1038/mp.2016.59
                PMC ID: 5444024
                PubMed ID: 27113998
                SO-VID: 6b7cc240-20b9-4ea0-9d93-f4662913e972
                Copyright © Copyright © 2016 Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                Date received : 17 September 2015
                Date revision received : 12 December 2015
                Date accepted : 20 January 2016
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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