Loss of Bin1 Promotes the Propagation of Tau Pathology
Open accessAbstract
Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer's disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking.
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In neurons, increased AMPH expression is associated with increased tau pathology, while increased BIN1 expression is associated with decreased tau pathology.
“In neurons, increased AMPH expression is associated with increased tau pathology, while increased BIN1 expression is associated with decreased tau pathology (36).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [36]
The mixed-culture results (p. 3) show that increased neuronal BIN1 isoform 1 expression decreases Tau aggregation and pathology propagation. The discussion (p. 8) describes a separate finding that loss of fly Amph rescues Tau-induced toxicity in the fly eye; it does not establish that increased AMPH expression in neurons is associated with increased Tau pathology. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBIN1 has been reported to potentially modulate the spreading of Tau aggregates through their internalization via endocytosis and endosomal trafficking.
“Notably, BIN1 has been reported to potentially modulate the spreading of Tau aggregates through their internalization via endocytosis and endosomal trafficking [14].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [14]
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 [479]
Extracellular tau can be taken up by neighboring cells, both neurons and glial cells, through various pathways including phagocytosis, macropinocytosis, receptor-mediated uptake, endocytosis, and/or membrane fusion of exosomes.
“Meanwhile, the extracellular tau can be taken up by neighboring cells, both neurons and glial cells, through various pathways, including phagocytosis [68], macropinocytosis [69], receptor-mediated uptake [67, 70], endocytosis [71], and/or membrane fusion of exosomes [72, 73].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [69]
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References 46 · Cited by 265
Research works printed but not linked: 1
- Braak, H., and Braak, E. (1991). Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol. 82 , 239-259. http://refhub.elsevier.com/S2211-1247(1631319-5/sref2)
- Authors
- Calafate, S., Flavin, W., Verstreken, P., & Moechars, D.
- Affiliations
- Janssen (Belgium) (BE)
- Loyola University Chicago (US)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Corresponding author
- Verstreken, Patrik
- Moechars, Diederik
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 17
- Issue
- 4
- Pages
- 931-940
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2536136445
- Cited by
- 265
- References
- 46
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 23 · 2023: 19 · 2022: 43 · 2021: 32 · 2020: 34 · 2019: 27 · 2018: 21 · 2017: 21 · 2016: 1
- FWCI
- 18.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Loyola University Chicago
- Belgian Federal Science Policy Office
- Fonds Wetenschappelijk Onderzoek
- Agentschap voor Innovatie door Wetenschap en Technologie
- Vlaamse regering
- Loyola University Chicago Stritch School of Medicine
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- BIN1, tau pathology, tau propagation, Alzheimer's disease, endocytosis, dynamin, endosomal trafficking, galectin-3, tau aggregates, neural circuits
- MeSH terms
- Animals, Cells, Cultured, Endocytosis, Intracellular Membranes, Nerve Tissue Proteins, Neurons, Endosomes, tau Proteins, Rats, Wistar, Protein Isoforms, Tauopathies, Tumor Suppressor Proteins, Dynamins, Adaptor Proteins, Signal Transducing, Protein Aggregates
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