The DOI matches its Crossref record; 155 of the 156 references it cites were found in a registry or an index, and 1 are not checked yet.
The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease
Open accessAbstract
Accumulation and aggregation of amyloid-β (Aβ) peptides in the brain trigger the development of progressive neurodegeneration and dementia associated with Alzheimer's disease (AD). Perturbation in Aβ clearance, rather than Aβ production, is likely the cause of sporadic, late-onset AD, which accounts for the majority of AD cases. Since cellular uptake and subsequent degradation constitute a major Aβ clearance pathway, the receptor-mediated endocytosis of Aβ has been intensely investigated. Among Aβ receptors, the low-density lipoprotein receptor-related protein 1 (LRP1) is one of the most studied receptors. LRP1 is a large endocytic receptor for more than 40 ligands, including apolipoprotein E, α2-macroglobulin and Aβ. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in brain Aβ clearance. LRP1 is highly expressed in a variety of cell types in the brain including neurons, vascular cells and glial cells, where LRP1 functions to maintain brain homeostasis and control Aβ metabolism. LRP1-mediated endocytosis regulates cellular Aβ uptake by binding to Aβ either directly or indirectly through its co-receptors or ligands. Furthermore, LRP1 regulates several signaling pathways, which also likely influences Aβ endocytic pathways. In this review, we discuss how LRP1 regulates the brain Aβ clearance and how this unique endocytic receptor participates in AD pathogenesis. Understanding of the mechanisms underlying LRP1-mediated Aβ clearance should enable the rational design of novel diagnostic and therapeutic strategies for AD.
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“Studies indicate that APOE binding is integral to some of these processes [16–20] with differences in APOE isoform-specific receptor binding affinity and lipid interactions affecting neuroinflammation, tau pathology, and amyloid plaque dynamics [21–24].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Collectively, these recent findings underscore the influence of APOE and APOE3Ch on both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LRP1 has the ability to endocytose an array of ligands, including apoE and Aβ, in a highly efficient manner, by coupling to other transmembrane proteins (5,10).”
From APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 (2019) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LRP1 mediates and regulates the endocytosis of > 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ) [21–27]”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [21]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LRP1 mediates and regulates the endocytosis of > 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ) [21–27]”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [26]
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“Receptors such as LRP1 can regulate APP endocytosis and amyloidogenic processing while also mediating cellular uptake and clearance of extracellular Aβ (Kanekiyo and Bu, 2014; Kanekiyo et al., 2013; Van Gool et al., 2019).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Kanekiyo and Bu, 2014
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“A major apoE receptor in the brain is LDL receptor-related protein 1 (LRP1), which is abundantly expressed in a variety of brain cell types in particular neurons.”
From APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 (2019) · cites this paper as [10]
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“because LRP1 plays a critical role in maintaining brain homeostasis (5,10).”
From APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 (2019) · cites this paper as [10]
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“neurons, astrocytes and microglia use LRP1 to uptake Aβ (28)”
From LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation (2023) · cites this paper as [28]
In the citing paper
“LRP1 and related receptors of the LDL receptor family are known to mediate endocytosis or phagocytosis of a wide range of extracellular targets, including Aβ, TAU, ApoE and apoptotic cells, via ligand binding to these receptors (6, 28, 52).”
From LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation (2023) · cites this paper as [28]
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1 retracted
RETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
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RetractedThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Self-citation2013 Alzheimer's disease facts and figures
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TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
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Lipopolysaccharide-induced neuroinflammation as a bridge to understand neurodegeneration
Batista, C. R. A., Gomes, G. F., Candelario-Jalil, E., Fiebich, B. L., & de Oliveira, A. C. P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092293 · Cited by 529
Metadata
- Authors
- Kanekiyo, T., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Kanekiyo, Takahisa
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-05-20
- Volume
- 6
- Pages
- 93-93
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC4033011
- OpenAlex
- W2003708432
- Cited by
- 281
- References
- 156
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 25 · 2023: 34 · 2022: 25 · 2021: 27 · 2020: 18 · 2019: 20 · 2018: 17 · 2017: 23 · 2016: 20 · 2015: 17 · 2014: 3
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging (P01AG030128, R01AG027924, RF1AG046205, R01AG046205, R01AG035355)
- National Institute of Neurological Disorders and Stroke (P01NS074969)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- LRP1, amyloid-beta clearance, Alzheimer's disease, receptor-mediated endocytosis, co-receptors, apolipoprotein E, alpha2-macroglobulin, amyloid-beta aggregation, neurodegeneration, glial cells, vascular cells, signaling pathways
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