BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation
| Autor: | Mikko Hiltunen, Idir Malki, Alessia Lasorsa, Amandine Flaig, Maxime Sartori, Yann Herault, Shruti Desai, Isabelle Landrieu, Mikael Marttinen, Jean-Charles Lambert, Tiago Mendes, Julien Chapuis, Philippe Amouyel, Jocelyn Laporte, Devrim Kilinc, Benoit Deprez, Anais-Camille Vreulx, Nicolas Malmanche, Laurent Pradier, Petra Mäkinen, Florence Leroux, Adrien Herldean, Damien Marechal, François-Xavier Cantrelle |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Genetically modified mouse
0303 health sciences Long-term memory Kinase Hippocampus Biology medicine.disease 3. Good health Cell biology Calcineurin 03 medical and health sciences 0302 clinical medicine medicine Phosphorylation Tauopathy Alzheimer's disease 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/462317 |
| Popis: | The bridging integrator 1 gene (BIN1) is a major genetic risk factor for Alzheimer’s disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (TgMAPT) or both human MAPT and BIN1 (TgMAPT;TgBIN1), which we followed-up from 3 to 15 months. In TgMAPT;TgBIN1 mice short-term memory deficits appeared earlier than in TgMAPT mice; however – unlike TgMAPT mice – TgMAPT;TgBIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After sacrifice of the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1-Tau interaction was also observed. We then sought mechanisms controlling the BIN1-Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1-Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified – among others – an inhibitor of Calcineurin, a Ser/Thr phosphatase. We determined that Calcineurin dephosphorylates BIN1 on a Cyclin-dependent kinase phosphorylation site at T348, promoting the open conformation of the neuronal BIN1 isoform. Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that the levels of the neuronal BIN1 isoform were decreased in AD brains, whereas phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory. |
| Databáze: | OpenAIRE |
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