Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid
Open accessAbstract
The mechanisms driving pathological beta-amyloid (Aβ) generation in late-onset Alzheimer's disease (AD) are unclear. Two late-onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Aβ generation in neurons. We identify a novel neuron-specific polarisation of Aβ generation controlled by Bin1 and CD2AP We discover that Bin1 and CD2AP control Aβ generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Aβ generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events. When Bin1 levels are reduced, BACE1 is trapped in tubules of early endosomes and fails to recycle in axons. When CD2AP levels are reduced, APP is trapped at the limiting membrane of early endosomes and fails to be sorted for degradation in dendrites. Hence, Bin1 and CD2AP keep APP and BACE1 apart in early endosomes by distinct mechanisms in axon and dendrites. Individuals carrying variants of either factor would slowly accumulate Aβ in neurons increasing the risk for late-onset AD.
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BIN1, CD2AP and PICALM modulate APP metabolism and the subsequent increase in Aβ production.
“Based on pathway enrichment analyses, three GWAS-defined genes linked with endocytosis (BIN1, CD2AP and PICALM) have been proposed to modulate APP metabolism and the subsequent increase in Aβ production:”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [137]
The section on downregulation of Bin1 and CD2AP reports altered APP processing and increased Aβ generation when those genes are depleted. The cited paper does not establish that PICALM has the same effect, nor does it present pathway-enrichment analyses as the basis for this finding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCD2AP depletion leads to trapping of APP in early endosomes and a subsequent increase in Aβ.
“CD2AP depletion leads to the trapping of APP in early endosomes and the subsequent increase in Aβ [137].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [137]
BIN1 depletion is associated with an increase in intracellular Aβ42, potentially through regulation of BACE1 trafficking and accumulation in early endosomes.
“BIN1 depletion was associated with an increase in intracellular Aβ42, potentially through the regulation of the β-secretase (BACE1) trafficking and accumulation in early endosomes [91, 137].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [137]
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Self-citation
- Authors
- Ubelmann, F., Burrinha, T., Salavessa, L., Gomes, R., Ferreira, C., Moreno, N., & Guimas Almeida, C.
- Affiliations
- Universidade Nova de Lisboa (PT)
- Instituto Gulbenkian de Ciência (PT)
- ORCID
- Venue
- The EMBO Reports
- Published
- 2016-11-28
- Volume
- 18
- Issue
- 1
- Pages
- 102-122
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC5210085
- OpenAlex
- W2557653052
- Cited by
- 165
- References
- 16
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 18 · 2023: 13 · 2022: 21 · 2021: 25 · 2020: 18 · 2019: 18 · 2018: 15 · 2017: 14 · 2016: 1
- FWCI
- 10.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação para a Ciência ea Tecnologia (Pest‐OE/EQB/LA0004/2013‐2014, INOVA4HEALTH ‐ UID/Multi/04462/2013, 01‐0145_FEDER‐007344, IF/00998/2012/CP0182/CT0004, RECI/BEX‐BCM/0083/2012, SFRH/BPD/94186/2013)
- Marie Curie Integration Grant (PCIG‐GA‐2012‐334366‐trafficinAD)
- Fondation pour la Recherche Médicale (SPE20130326599)
- Federación Española de Enfermedades Raras (PT2020)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BIN1, CD2AP, Alzheimer's disease, APP, BACE1, early endosomes, endosomal trafficking, axon-dendrite polarity, protein sorting, APP processing, genetic risk factors
- MeSH terms
- Animals, Axons, Cell Membrane, Cytoskeletal Proteins, Endocytosis, Female, Gene Expression Regulation, Male, Nerve Tissue Proteins, Neurons, Endosomes, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Mice, Amyloid Precursor Protein Secretases, Gene Knockdown Techniques
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