Tackling Alzheimer’s Disease pathology by modulating the binding of Tau to synaptic vesicles

Abstract

Event Abstract Back to Event Tackling Alzheimer’s Disease pathology by modulating the binding of Tau to synaptic vesicles Pablo Largo-Barrientos1, 2*, Valerie Uytterhoeven1, 2 and Patrik Verstreken1, 2 1 KU Leuven, Belgium 2 VIB & KU Leuven Center for Brain & Disease Research, Belgium Microtubule-associated protein Tau is implicated in more than 20 neurodegenerative disorders, including Alzheimer's Disease (AD). The association of Tau and AD was first established after the observation of neurofibrilarily tangles inside the neurons of AD patients' brains which were composed mostly of Tau protein aggregates. Since then, most of the research has focused on the process of aggregation of tau and most of the attempts to interfere with Tau pathology have aimed to prevent this aggregation. However, aggregation of Tau does not always correlate well with the cognitive decline and memory loss associated with AD. Recent evidence has shown that before the formation of aggregates, soluble pathogenic Tau protein induces synaptic dysfunction and loss of synapses, a process that correlates much better with cognitive and memory impairment and thus seems to be a more promising therapeutic target than Tau aggregation. Our lab has recently published that Tau-induced synaptic dysfunction is a consequence of the binding of soluble Tau to synaptic vesicles at presynaptic terminals, a binding that occurs via the interaction of Tau with the synaptic vesicle-associated protein Synaptogyrin-3. When vesicles are sequestered by pathogenic Tau, they show reduced mobility and neurotransmitter release is severely impaired (Figure 1). However, reducing the levels of Synaptogyrin-3 in flies and mouse primary neurons has proven to be effective in rescuing these Tau-induced synaptic defects. Our goal is to investigate whether reverting presynaptic Tau-induced toxicity by disrupting the interaction between Tau and Synaptogyrin-3 is a good strategy to tackle later aspects of Tau pathology. In other words, we know that lowering the levels of Syngr3 rescues neurotransmitter release defects induced by presynaptic tau in flies and mouse primary neurons, but we do not know if this also rescues tau-induced neurodegeneration and behavioural/cognitive defects. For this purpose we are currently following two strategies. Firstly, we have generated a Synaptogyrin-3 knockout mouse that have been crossed to a pathogenic human Tau overexpressing mouse. We are now evaluating whether mice overexpressing pathogenic human Tau with reduced Synaptogyrin-3 expression levels (heterozygous knockout) show a rescue in synaptic dysfunction, memory decline and neurodegeneration. Secondly, we establishing a biochemical and a cellular-based assay to perform high throughput screening for compounds that can break the interaction of Tau and Synaptogyrin-3 and could be potentially relevant from a clinical perspective. In conclusion, our research will provide insight into the contribution of Tau-induced presynaptic dysfunction in AD onset and progression and we could develop a compound to tackle this specific aspect of the disease. Figure 1 References McInnes J, Wierda K, Snellinx A, et al. Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. Neuron. 2018;97(4):823-835.e8. doi:10.1016/j.neuron.2018.01.022 Zhou L, McInnes J, Wierda K, et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nat Commun. 2017;8:15295. doi:10.1038/ncomms15295 Keywords: tau, synaptic vesicle, Synaptic Function, mouse model, Compound screening Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018. Presentation Type: e-posters Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE Citation: Largo-Barrientos P, Uytterhoeven V and Verstreken P (2019). Tackling Alzheimer’s Disease pathology by modulating the binding of Tau to synaptic vesicles. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00090 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 Aug 2018; Published Online: 17 Jan 2019. * Correspondence: Mr. Pablo Largo-Barrientos, KU Leuven, Leuven, Belgium, pablo.largobarrientos@kuleuven.vib.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Pablo Largo-Barrientos Valerie Uytterhoeven Patrik Verstreken Google Pablo Largo-Barrientos Valerie Uytterhoeven Patrik Verstreken Google Scholar Pablo Largo-Barrientos Valerie Uytterhoeven Patrik Verstreken PubMed Pablo Largo-Barrientos Valerie Uytterhoeven Patrik Verstreken Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.