Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology
Open accessAbstract
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
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Previous studies using the same antibodies employed in this analysis identified similar immunolabeling in the human brain as reported here, but attributed the labeling to neuronal soma or nucleus without comparing BIN1 immunolabeling with markers for neurons or oligodendrocytes.
“Previous studies using the same antibodies employed in our analysis identified similar immunolabeling in the human brain as reported here, but attributed the labeling to neuronal soma or nucleus without comparing BIN1 immunolabeling with markers for neurons or oligodendrocytes [13, 26, 30].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Experimental — accuracy not yet measuredNo overlap in the cellular expression of BIN1 and Iba1 was observed in the hippocampus of patients with AD.
“Similar to our findings, no overlap in the cellular expression of BIN1 and Iba1 was observed in the hippocampus of patients with AD [26].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
The Results section reports that BIN1 was mainly present in neurons and only rarely observed in microglia in AD brain tissue. The Immunohistochemistry section specifies hippocampal sections and use of an Iba1 antibody. These passages support limited BIN1–microglia overlap, but not the categorical claim that no overlap was observed. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPartial or total loss of Amphiphysin expression attenuated the rough eye phenotype induced by overexpression of human Tau but not Aβ42 in Drosophila eye.
“partial or total loss of Amphiphysin expression attenuated the rough eye phenotype induced by the overexpression of human Tau but not Aβ42 in Drosophila eye.”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
The Results section reports that Amph knockdown attenuated the human Tau-induced rough-eye phenotype in Drosophila, while altered Amph expression did not modify the Aβ42-induced phenotype. The Tau experiment also used flies heterozygous for an Amph null allele, so it does not establish that total loss of Amph expression attenuated the Tau phenotype. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBIN1 has been identified as the first AD genetic risk factor linked to Tau pathology.
“BIN1, which has been identified as the first AD genetic risk factor linked to Tau pathology.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [18]
The Discussion reports evidence linking BIN1-related AD risk to Tau biology, but qualifies the priority claim: “If confirmed, BIN1 would be the first genetic risk factor for AD linked to the ‘Tau pathway’.” The citing sentence presents that tentative conclusion as an established identification. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIt is generally assumed, and in a few papers described, that BIN1 is expressed in neurons.
“The findings detailed above were surprising because it is generally assumed, and in a few papers described, that BIN1 is expressed in neurons [4, 26, 30].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
Two studies reported significantly increased BIN1 transcript levels in brains of individuals with AD.
“While two studies have reported significantly increased BIN1 transcripts levels in brains of individuals with AD [26, 31]”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
A previous study showed an interaction between fly Amphiphysin and human Tau in a fly model of AD Tau pathology.
“A previous study showed an interaction between fly Amphiphysin and human Tau in a fly model of AD Tau pathology [26].”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [26]
A functional risk variant of BIN1 is associated with Tau loads but not Aβ loads in AD brains.
“a functional risk variant of BIN1 has been associated with Tau loads (but not Aβ loads) in AD brains [18].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [18]
Loss- and gain-of-function of the Drosophila ortholog of BIN1 modified the rough eye phenotype induced by human Tau expression.
“Loss- and gain-of-function of the Drosophila ortholog of BIN1 modified the rough eye phenotype induced by human Tau expression [18].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [18]
For the 24 signals reported, other evidence indicates that APOE, ABCA7, BIN1, TREM2, SORL1, ADAM10, SPI1, and CR1 are the true Alzheimer's disease risk genes.
“For the 24 signals reported here, other evidence indicates that APOE35,36, ABCA7 (refs. 37–40), BIN1 (ref. 41), TREM2 (refs. 7,8), SORL1 (refs. 42,43), ADAM10 (ref. 44), SPI1 (ref. 45), and CR1 (ref. 46) are the true Alzheimer’s disease risk gene”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [41]
Neuronal FcγRIIb binds Aβ42 with high affinity and mediates neurotoxicity and memory impairment triggered by Aβ.
“Neuronal FcγRIIb can bind to Aβ42 with a high affinity, and mediate neurotoxicity and memory impairment triggered by Aβ [240, 376–380].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [376]
BIN1 expression is elevated in AD patients.
“Some studies have shown that BIN1 expression is elevated in AD patients [376, 477].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [376]
BIN1 transcript level is increased in AD brains.
“whose transcript level is increased in AD brains48 (Fig. 4b).”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [48]
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- Authors
- GERAD consortium, Chapuis, J., Hansmannel, F., Gistelinck, M., Mounier, A., Van Cauwenberghe, C., Kolen, K. V., Geller, F., Sottejeau, Y., Harold, D., Dourlen, P., Grenier-Boley, B., Kamatani, Y., Delepine, B., Demiautte, F., Zelenika, D., Zommer, N., Hamdane, M., Bellenguez, C., Dartigues, J.-F., Hauw, J.-J., Letronne, F., Ayral, A.-M., Sleegers, K., Schellens, A., Broeck, L. V., Engelborghs, S., De Deyn, P. P., Vandenberghe, R., O'Donovan, M., Owen, M., Epelbaum, J., Mercken, M., Karran, E., Bantscheff, M., Drewes, G., Joberty, G., Campion, D., Octave, J.-N., Berr, C., Lathrop, M., Callaerts, P., Mann, D., Williams, J., Buée, L., Dewachter, I., Van Broeckhoven, C., Amouyel, P., Moechars, D., Dermaut, B., & Lambert, J.-C.
- Affiliations
- Inserm (FR)
- KU Leuven (BE)
- Janssen (Belgium) (BE)
- Cardiff University (GB)
- Fondation Jean Dausset-CEPH (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- University of Antwerp (BE)
- Universitair Ziekenhuis Leuven (BE)
- UCLouvain (BE)
- University of Manchester (GB)
- Corresponding author
- Dermaut, B
- Lambert, J-C
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2013-02-12
- Volume
- 18
- Issue
- 11
- Pages
- 1225-1234
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3807661
- OpenAlex
- W2121312696
- Cited by
- 407
- References
- 24
- Citations by year
- 2026: 16 · 2025: 28 · 2024: 38 · 2023: 27 · 2022: 43 · 2021: 34 · 2020: 43 · 2019: 37 · 2018: 33 · 2017: 27 · 2016: 32 · 2015: 19 · 2014: 21 · 2013: 9
- FWCI
- 18.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Juvenile Diabetes Research Foundation International
- Alzheimer's Association (IIRG-06-25487)
- Sanofi
- Wellcome Trust
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Université de Lille
- Alzheimer's Society
- Alzheimer's Research Trust
- Cardiff University
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung
- Fonds De La Recherche Scientifique - FNRS
- Belgian Federal Science Policy Office
- Fonds Wetenschappelijk Onderzoek
- Eisai
- Fondation de France
- Alfried Krupp von Bohlen und Halbach-Stiftung
- Universiteit Antwerpen
- Mutuelle Générale de l'Education Nationale
- University College London Hospitals NHS Foundation Trust
- Vlaamse regering
- H. Lundbeck A/S
- Instituut Born-Bunge
- Heinz Nixdorf Stiftung
- National Institutes of Health
- Medical Research Council (MR/K013041/1)
- Menzies Centre for Australian Studies, King's College London, University of London
- Bijzonder Onderzoeksfonds UGent
- European Regional Development Fund
- National Institute on Aging
- National Institute of Mental Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development
- 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, Alzheimer's disease, genetic susceptibility, tau pathology, transcriptional regulation, amyloid, neuroblastoma cells
- MeSH terms
- Alzheimer Disease, Animals, Brain, Carrier Proteins, Cells, Cultured, Drosophila melanogaster, Humans, Nerve Degeneration, Nuclear Proteins, Synaptosomes, Transcription Factors, Gene Expression, Case-Control Studies, tau Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Mice, Endophenotypes, Plaque, Amyloid
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