BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation
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.
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BibTeX
@article{sartori2026bin1,
title = {{BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation}},
author = {Maxime Sartori and Tiago P. Mendes and Shruti Desai and Alessia Lasorsa and Adrien Herledan and Nicolas Malmanche and Petra Mäkinen and Mikael Marttinen and Idir Malki and Julien Chapuis and Amandine Flaig and Anaïs-Camille Vreulx and Marion Ciancia and Philippe Amouyel and Florence Leroux and Benoit Déprez and François-Xavier Cantrelle and Damien Marechal and Laurent Pradier and Mikko Hiltunen and Isabelle Landrieu and Devrim Kilinc and Yann Hérault and Jocelyn Laporte and Jean-Charles Lambert},
journal = {Acta Neuropathologica},
year = {2026},
month = oct,
doi = {10.1007/s00401-019-02017-9},
url = {https://hal.science/hal-02337166v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation
AU - Maxime Sartori
AU - Tiago P. Mendes
AU - Shruti Desai
AU - Alessia Lasorsa
AU - Adrien Herledan
AU - Nicolas Malmanche
AU - Petra Mäkinen
AU - Mikael Marttinen
AU - Idir Malki
AU - Julien Chapuis
AU - Amandine Flaig
AU - Anaïs-Camille Vreulx
AU - Marion Ciancia
AU - Philippe Amouyel
AU - Florence Leroux
AU - Benoit Déprez
AU - François-Xavier Cantrelle
AU - Damien Marechal
AU - Laurent Pradier
AU - Mikko Hiltunen
AU - Isabelle Landrieu
AU - Devrim Kilinc
AU - Yann Hérault
AU - Jocelyn Laporte
AU - Jean-Charles Lambert
PY - 2026
DA - 2026/10/30
JO - Acta Neuropathologica
DO - 10.1007/s00401-019-02017-9
UR - https://hal.science/hal-02337166v1
AB - 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.
SN - 0001-6322
SN - 1432-0533
ER -