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Acta Neuropathol. 2019 May 7. doi: 10.1007/s00401-019-02017-9. [Epub ahead of print]

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation.

Sartori M1,2,3,4, Mendes T5,6,7,8, Desai S5,6,7, Lasorsa A7,9, Herledan A6,10,11, Malmanche N5,6,7, Mäkinen P12, Marttinen M12, Malki I7,9, Chapuis J5,6,7, Flaig A5,6,7, Vreulx AC5,6,7, Ciancia M1,2,3,4, Amouyel P5,6,7, Leroux F6,10,11, Déprez B6,10,11, Cantrelle FX7,9, Maréchal D1,2,3,4, Pradier L8, Hiltunen M12, Landrieu I7,9, Kilinc D5,6,7, Herault Y13,14,15,16, Laporte J17,18,19,20, Lambert JC21,22,23.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France.
2
INSERM U1258, Illkirch, France.
3
CNRS UMR7104, Illkirch, France.
4
Strasbourg University, Illkirch, France.
5
INSERM U1167, RID-AGE: Risk Factors and Molecular Determinants of Aging-Related Diseases, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019, Lille, France.
6
Institut Pasteur de Lille, Lille, France.
7
University of Lille, DISTALZ Laboratory of Excellence (LabEx), Lille, France.
8
SANOFI Neuroscience Therapeutic Area, Chilly-Mazarin, France.
9
CNRS UMR8576, Lille, France.
10
University of Lille, EGID, Lille, France.
11
INSERM U1177, Drugs and Molecules for Living Systems, Lille, France.
12
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
13
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France. herault@igbmc.fr.
14
INSERM U1258, Illkirch, France. herault@igbmc.fr.
15
CNRS UMR7104, Illkirch, France. herault@igbmc.fr.
16
Strasbourg University, Illkirch, France. herault@igbmc.fr.
17
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France. jocelyn@igbmc.fr.
18
INSERM U1258, Illkirch, France. jocelyn@igbmc.fr.
19
CNRS UMR7104, Illkirch, France. jocelyn@igbmc.fr.
20
Strasbourg University, Illkirch, France. jocelyn@igbmc.fr.
21
INSERM U1167, RID-AGE: Risk Factors and Molecular Determinants of Aging-Related Diseases, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019, Lille, France. jean-charles.lambert@pasteur-lille.fr.
22
Institut Pasteur de Lille, Lille, France. jean-charles.lambert@pasteur-lille.fr.
23
University of Lille, DISTALZ Laboratory of Excellence (LabEx), Lille, France. jean-charles.lambert@pasteur-lille.fr.

Abstract

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 killing 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 although the levels of the neuronal BIN1 isoform were unchanged in AD brains, 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.

KEYWORDS:

Alzheimer’s disease; BIN1; Calcineurin; Cdk; High-content screening; Long-term memory; Neurodegeneration; Nuclear magnetic resonance; Proximity ligation assay; Tau; Tauopathy

PMID:
31065832
DOI:
10.1007/s00401-019-02017-9

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