BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation
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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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BIN1 overexpression reverses memory deficits in tau transgenic mice, and neuronal BIN1 expression is inversely correlated with pathological tau propagation.
“BIN1 overexpression has been shown to reverse memory deficits in tau transgenic mice, and neuronal BIN1 expression is inversely correlated with pathological tau propagation [478, 479].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [478]
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Alzheimer's Disease: Tau Pathology and Dysfunction of Endocytosis
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“Tau is associated with some of these endocytic proteins such as BIN1 (Calafate et al., 2016; Sartori et al., 2019), PICALM (Ando et al.”
BackgroundInfluentialPerdigão, C., Barata, M. A., Burrinha, T., & Almeida, C. G. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101056 · Cited by 33 · see citing works
“Both mutations may also interfere with neuronal Bin1 selfinhibition through the intramolecular binding between the CLAP domain and the SH3 domain (46).”
BackgroundMechanical regulation of synapse formation and plasticity
Minegishi, T., Kastian, R. F., & Inagaki, N. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.017 · Cited by 37 · see citing works
Glennon, E. B. C., Lau, D. H. W., Gabriele, R. M. C., Taylor, M. F., Troakes, C., Opie-Martin, S., Elliott, C., Killick, R., Hanger, D. P., Perez‐Nievas, B. G., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa011 · Cited by 33 · see citing works
“This finding is in agreement with previous reports that over-expression of BIN1 in mice expressing human tau leads to a reduced number of somatodendritic tau inclusions (Sartori et al., 2019).”
BackgroundResultInfluentialCarroll, T., Guha, S. K., Nehrke, K. W., & Johnson, G. V. W. (2021) · Biology · doi:10.3390/biology10101047 · Cited by 35 · see citing works
A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity
Rush, T., Roth, J. R., Thompson, S. J., Aldaher, A. R., Cochran, J. N., & Roberson, E. D. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104668 · Cited by 30 · see citing works
Kilinc, D., Vreulx, A.-C., Mendes, T., Flaig, A., Coelho, D. M., Verschoore, M., Demiautte, F., Amouyel, P., Bank, N.-C. B., Eysert, F., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa139 · Cited by 27 · see citing works
“Primary neurons were obtained from P0 rats, according to previously described procedures (Sartori et al., 2019).”
MethodSelf-citationCell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo
McAvoy, K. M., Sait, H. R., Marsh, G., Peterson, M. A., Reynolds, T. L., Gagnon, J., Geisler, S. B., Leach, P. T., Roberts, C., Cahir-McFarland, E. D., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220125 · Cited by 26 · see citing works
The Mechanistic Role of Bridging Integrator 1 (BIN1) in Alzheimer’s Disease
Gao, P.-R., Ye, L., Cheng, H.-R., & Li, H. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00926-y · Cited by 28 · see citing works
Hu, H., Tan, L., Bi, Y., Xu, W., Tan, L., Shen, X., Hou, X., Ma, Y., Dong, Q., & Yu, J. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01218-9 · Cited by 25 · see citing works
Cell type-specific functions of Alzheimer's disease endocytic risk genes
Maninger, J., Nowak, K., Goberdhan, S., O’Donoghue, R., & Connor‐Robson, N. (2024) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0378 · Cited by 21 · see citing works
BIN1 and Alzheimer’s disease: the tau connection
Dourlen, P., Kilinc, D., Landrieu, I., Chapuis, J., & Lambert, J. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.03.004 · Cited by 23 · see citing works
Self-citationAkram, Z., Ahmed, I., Mack, H., Kaur, R., Silva, R. C., Castilho, B. A., Friant, S., Sattlegger, E., & Munn, A. (2020) · Cells · doi:10.3390/cells9030672 · Cited by 20 · see citing works
Genome-wide association study in Alzheimer’s disease: a bibliometric and visualization analysis
Zhang, J., Wang, Y., Zhang, Y., & Yao, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1290657 · Cited by 21 · see citing works
Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?
Wang, J., Zhen, Y., Yang, J., Yang, S., & Zhu, G. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14688 · Cited by 16 · see citing works
“62,99 BIN1 is expressed in various cells in the brain, including neurons and glial cells, and plays a variety of biological activities.”
BackgroundMarked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer’s-Type Tau Pathology
Cho, J. D., Kim, Y. A., Rafikian, E. E., Yang, M., & Santa‐María, I. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.634157 · Cited by 16 · see citing works
Jin, Y., Zhao, L., Zhang, Y., Chen, T., Shi, H., Sun, H., Ding, S., Chen, S., Cao, H., Zhang, G., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2393932 · Cited by 14 · see citing works
“BIN1 directly interacts with MAPT/Tau via its C-terminal SH3 domain [9,10]; in various cellular and mouse models, BIN1 regulates MAPT/ Tau pathology, the transcellular spreading of MAPT/Tau [9,11,12], and MAPT/Tau-dependent neuronal network excitability [13].”
Leung, S. K., Bamford, R. A., Jeffries, A. R., Castanho, I., Chioza, B. A., Flaxman, C. S., Moore, K., Dempster, E. L., Harvey, J., Brown, J. T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50486-8 · Cited by 18 · see citing works
“As reported for the human BIN1 gene 27 , the inclusion of exons 14 – 16, which encode the conserved CLAP domain involved in endocytosis 28 , was highly variable among Bin1 transcripts in the mouse cortex (exon 14 skipping: n =326 isoforms, exon 15 skipping: n =242 isoforms, exon 16skipping: n…”
Alzheimer’s genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses
Barata, M. A., Perdigão, C., Ramalho, J. S., Gomes, E. R., & Almeida, C. G. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116005 · Cited by 9 · see citing works
Lehrer, S., & Rheinstein, P. H. (2020) · American Journal of Clinical Oncology · doi:10.1097/coc.0000000000000727 · Cited by 9 · see citing works
Biofluid biomarkers for Alzheimer’s disease
Wang, S., Xie, S., Zheng, Q., Zhang, Z., Wang, T., & Zhang, G. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1380237 · Cited by 8 · see citing works
Molecular mechanisms of aging in the pathogenesis of Alzheimer’s disease
Kakkar, A., Singh, H., Singh, B. K., Chauhan, K., Chopra, S., Chopra, H., & Mishra, A. K. (2026) · Discover Neuroscience · doi:10.1186/s13064-026-00243-y · Cited by 9 · see citing works
Kretzschmar, G. C., Alencar, N. M., da Silva, S. S. L., Sulzbach, C. D., Meissner, C. G., Petzl‐Erler, M. L., de Souza, R. L. R., & Boldt, A. B. W. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.632314 · Cited by 8 · see citing works
Lu, S., Qiu, S., Yu, G., Zhang, A., & Zhao, Q. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103097 · Cited by 8 · see citing works
Leung, S. K., Jeffries, A. R., Castanho, I., Bamford, R. A., Moore, K., Dempster, E. L., Brown, J. T., Ahmed, Z., O’Neill, P., Hannon, E. J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.20.558220 · Cited by 7 · see citing works
BIN1 in the Pursuit of Ousting the Alzheimer’s Reign: Impact on Amyloid and Tau Neuropathology
Kaur, I., Behl, T., Sundararajan, G., Panneerselvam, P., Vijayakumar, A. R., Senthilkumar, G. P., Venkatachalam, T., Jaglan, D., Yadav, S., Anwer, K., et al. (2023) · Neurotoxicity Research · doi:10.1007/s12640-023-00670-3 · Cited by 6 · see citing works
“However, in late-onset AD models, the levels of BIN1 protein are either found to be alleviated (Glennon and Whitehouse 2013; Glennon et al. 2020) or unaltered (Sartori et al. 2019).”
BackgroundAmyloid‐β but not tau accumulation is strongly associated with longitudinal cognitive decline
Wang, W., Huang, J., Qian, S., Zheng, Y., Yu, X., Jiang, T., Ai, R., Hou, J., Ma, E., Cai, J., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14860 · Cited by 5 · see citing works
Thomas, S., & Prendergast, G. C. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1183932 · Cited by 7 · see citing works
“, 2011) that directly bind to the Bin1 SH3 domain in a phosphorylation-dependent manner (Chapuis et al., 2013; Sottejeau et al., 2015; Malki et al., 2017; Sartori et al., 2019).”
BackgroundLatina, V., Atlante, A., Malerba, F., Regina, F. L., Balzamino, B. O., Micera, A., Pignataro, A., Stigliano, E., Cavallaro, S., Calissano, P., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119683 · Cited by 5 · see citing works
“Interestingly, BIN1 directly binds to the proline-rich domain of tau via its SH3 domain [147,150,151] and interferes with its neurotoxicity, both in cellular and mouse models [69,152,153].”
BackgroundCo-occurrent Alterations of Alzheimer's Genes and Prostate Cancer Genes in Prostate Cancer
LEHRER, S., & Rheinstein, P. H. (2020) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20187 · Cited by 5 · see citing works
Proteomic Characterization of the Alzheimer’s Disease Risk Factor BIN1 Interactome
McMillan, J. D., Wang, S., Wohlfahrt, J., Guergues, J., Stevens, S. M., & Thinakaran, G. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101055 · Cited by 4 · see citing works
“Interacting Partner that Facilitates Endocytosis at the Synapse Kinases function as molecular switches in many biological processes, and BIN1 itself undergoes phosphorylation (24, 39).”
Mendes, T., Herlédan, A., Leroux, F., Deprez, B. P., Lambert, J., & Kilinc, D. (2019) · Current Protocols in Cell Biology · doi:10.1002/cpcb.100 · Cited by 4 · see citing works
“Despite these limitations, this protocol allowed us to identify modulators of the BIN1-tau interaction in neurons, two of which we were able to confirm via complementary techniques (Sartori et al., 2019).”
BackgroundMethodSelf-citationEndocytic scaffolds at the crossroads of Alzheimer’s disease and neuronal aging
Shergill, J. K., & Tehran, D. A. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0250 · Cited by 2 · see citing works
“…role as a membrane-remodeling protein in AD, a direct interaction was reported between the SH3 domains of BINiso1 and BINIso9 and tau (Malki et al. 2017) (Figure 3), and this interaction is modulated by the phosphorylation status of both tau (Sottejeau et al. 2015) and BIN1 (Sartori et al. 2019).”
Ranganathan, R., Li, S., Sapozhnikov, G., Wang, S., & Song, Y. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823241296018 · Cited by 2 · see citing works
Li, X., Zhang, Y., Chen, X., Yuan, H., Wang, Z., Wang, G., Zhang, K., & Liu, H. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.753909 · Cited by 2 · see citing works
“As one of the most stable genetic risk factors for DAT, BIN1 is overexpressed in patient brains (22).”
BackgroundKilinc, D., Vreulx, A.-C., Mendes, T., Flaig, A., Coelho, D. M., Verschoore, M., Demiautte, F., Amouyel, P., Bank, N.-C. B., Eysert, F., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.20.884205 · Cited by 2 · see citing works
“Primary neurons were obtained from P0 rats, according to previously described procedures (Sartori et al., 2019).”
MethodSelf-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Davoine, L., Dupont, C., Amouyel, P., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.02.438184 · Cited by 2 · see citing works
Self-citationDuckhorn, J. C., Kim, D. K., & Huang, Y. A. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00243 · Cited by 2 · see citing works
Maaser‐Hecker, A., Zellmer, J. C., Kim, M. M., Bakiasi, G., Maiti, A. K., Curtat, M. P. C., Choi, S. H., Prokopenko, D., Tanzi, R. E., & Bhattacharyya, R. (2026) · Science Advances · doi:10.1126/sciadv.adx2127 · Cited by 2 · see citing works
実験核物理領域,理論核物理領域「LHCとRHICの競演が拓く新世代のクォーク・グルーオン・プラズマ物性」(2012年秋季大会シンポジウムの報告,学会報告)
佐藤, 進. (2013) · 日本物理學會誌
Chan, D., Spires‐Jones, T. L., Provenzano, F. A., Glennon, E. B. C., & Duff, K. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780190065324.003.0020
BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicityPreprint
Lambert, E., Gelle, C., Leclerc, V., Freire‐Regatillo, A., Barois, N., Malfoi, T., Hermant, X., Demiautte, F., Lafont, F., Amouyel, P., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.11.669624
“Primary neurons were obtained from P0 (post-natal day 0) rats according to established procedures (Sartori et al., 2019).”
Self-citationBIN1 deficiency leads to DNA damage and neuronal insulin resistance through ATM dysregulationPreprint
Jin, Y., Shi, H., Zhao, L., Zhang, G., Ding, S., Wu, Y., Fan, W., Liu, Z., Ruan, H., Li, Y., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.20.671271
“6-8 BIN1 directly interacts with TAU, 9-11 and regulates intercellular propagation of TAU pathology; 12 overexpression of BIN1 induces neuronal network hyperexcitability in a TAU-dependent manner.”
Detection of Protein – Protein Interactions In Situ via Proximity Ligation Assay
Zhou, X., & Zou, P. (2025) · doi:10.1002/9783527845828.ch5
Moncheaux, A., Guimond, A., Spiegelhalter, C., Messaddeq, N., Nahy, C., & Laporte, J. (2026) · Human Molecular Genetics · doi:10.1093/hmg/ddag082
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093090
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093108
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093111
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093117
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093105
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093096
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093093
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093099
Self-citationLambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093102
Self-citationBIN1 (amphiphysin 2) in the pathogenesis of cognitive impairment
Shamakina, I. Y., Kokhan, V. S., Venkova, V. A., Баронец, В. Ю., Popov, S. S., & Anokhin, P. K. (2026) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202612603145
BIN1 (Amphiphysin 2) in the Pathogenesis of Cognitive Impairment
Shamakina, I. Y., Kokhan, V. S., Venkova, V. A., Баронец, В. Ю., Popov, S. S., & Anokhin, P. K. (2026) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-026-02059-z
Peregud, D., Pavlova, O., Ka, P., Nebogina, K., Zorkina, Y., Abramova, O. V., Ushakova, V. M., Ochneva, A., Zubkov, E. A., Shamakina, I. Y., et al. (2026) · Diseases · doi:10.3390/diseases14100368
- Authors
- Sartori, M., Mendes, T., Desai, S., Lasorsa, A., Herledan, A., Malmanche, N., Mäkinen, P., Marttinen, M., Malki, I., Chapuis, J., Flaig, A., Vreulx, A.-C., Ciancia, M., Amouyel, P., Leroux, F., Déprez, B., Cantrelle, F.-X., Maréchal, D., Pradier, L., Hiltunen, M., Landrieu, I., Kilinc, D., Herault, Y., Laporte, J., & Lambert, J.-C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Eastern Finland (FI)
- Sanofi (France) (FR)
- Corresponding author
- Laporte, Jocelyn
- Lambert, Jean-Charles
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2019-05-07
- Volume
- 138
- Issue
- 4
- Pages
- 631-652
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC6778065
- OpenAlex
- W2951997054
- Cited by
- 72
- References
- 58
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 9 · 2019: 7 · 2013: 1
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (15-CE-16-0002, 10-INBS-07694)
- Alzheimer's association (BFG-14-318355)
- Academy of Finland (307866)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BIN1, tauopathy, Alzheimer's disease, tau phosphorylation, calcineurin, cyclin-dependent kinases, SH3 domain, long-term memory deficits, short-term memory impairment, hippocampus, transgenic mice, high-content screening
- MeSH terms
- Alzheimer Disease, Animals, Brain, Memory Disorders, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Phosphorylation, tau Proteins, Tauopathies, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Mice, Memory, Long-Term, Spatial Memory
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