Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression
Open accessAbstract
In Alzheimer's disease, soluble amyloid-β causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-β are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-β expressed on myeloid cells. To determine the role of Scara1 in clearance of soluble amyloid-β in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer's disease, and generate PS1-APP-Scara1-deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation, leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer's disease.
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Msr1 mediates endocytosis of low-density lipoproteins and is involved in uptake and degradation of amyloid beta.
“Msr1 mediates endocytosis of low-density lipoproteins (LDLs) and is involved in uptake and degradation of amyloid b (Ab)”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Frenkel et al., 2013
The Results section ('Scara1 deficiency is associated with reduced sAβ uptake'; page unavailable) identifies Scara1 as a major receptor for soluble amyloid-β uptake, and another Results section links reduced uptake to reduced amyloid-β degradation. The Discussion says Scara1 mediates adhesion to oxidized-LDL-coated surfaces, but does not establish that it mediates LDL endocytosis. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAβ clearance involves microglial phagocytosis and endocytosis via scavenger receptors and extracellular degradation by Aβ-degrading enzymes.
“Aβ clearance involves, in part36, phagocytosis and endocytosis via microglial scavenger receptors (SRs)37,38 and extracellular degradation by Aβ-degrading enzymes6,36.”
From Microglia in neurodegeneration (2018) · cites this paper as [37]
Loss of SR-A1 lowers microglial Aβ uptake by 60% and raises mortality and Aβ accumulation.
“SR-A1-deficiency decreases microglial Aβ uptake by 60%37,136 and increases mortality and Aβ accumulation37,136”
From Microglia in neurodegeneration (2018) · cites this paper as [37]
Microglia around Aβ plaques in humans and Aβ-mice express SR-A1, a receptor that phagocytoses Aβ.
“SR-A1 is an Aβ-phagocytic receptor37,38 expressed on microglia surrounding Aβ plaques in humans and Aβ-mice.”
From Microglia in neurodegeneration (2018) · cites this paper as [37]
Increasing SR-A in Aβ-mice reduces Aβ burden.
“whereas upregulation of SR-A leads to reduced Aβ burden in Aβ-mice37.”
From Microglia in neurodegeneration (2018) · cites this paper as [37]
Blood-based biomarkers have become the primary goal in screening for and diagnosing AD in the population, and many studies focus on examining the role of peripheral Aβ and APP in AD development.
“Considering the greater availability of blood sampling, blood-based biomarkers become the primary goal in screening for and diagnosing AD in the population and many studies now focus on examining the role of peripheral Aβ and APP in AD development.267–269”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [268]
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- Authors
- Frenkel, D., Wilkinson, K., Zhao, L., Hickman, S. E., Means, T. K., Puckett, L., Farfara, D., Kingery, N. D., Weiner, H. L., & El Khoury, J.
- Affiliations
- Tel Aviv University (IL)
- Brigham and Women's Hospital (US)
- Corresponding author
- Frenkel, Dan
- ORCID
- Venue
- Nature Communications
- Published
- 2013-06-25
- Volume
- 4
- Issue
- 1
- Pages
- 2030-2030
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3702268
- OpenAlex
- W2132663452
- Cited by
- 214
- References
- 40
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 22 · 2023: 16 · 2022: 15 · 2021: 29 · 2020: 21 · 2019: 21 · 2018: 12 · 2017: 10 · 2016: 11 · 2015: 15 · 2014: 12 · 2013: 4
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Alzheimer's Association
- Dana Foundation
- Israel Science Foundation
- National Institutes of Health
- National Institute on Aging (R01AG043975, AG032349, AG043975, R01AG032349)
- National Institute of Allergy and Infectious Diseases (AI082660, R01AI084884, U24AI082660)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Institute of Neurological Disorders and Stroke (NS059005, R01NS059005)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- soluble amyloid-beta, Alzheimer's disease, amyloid-beta clearance, scavenger receptors, mononuclear phagocytes, microglia, macrophages, amyloid-beta aggregation, amyloid-beta deposition
- MeSH terms
- Alzheimer Disease, Animals, Cysteine Endopeptidases, Drug Combinations, Humans, Leukocytes, Mononuclear, Lipopolysaccharides, Macrophages, Phagocytes, Solubility, Up-Regulation, Survival Analysis, Amyloid beta-Peptides, Microglia, Disease Progression, CD36 Antigens, RNA, Small Interfering, Scavenger Receptors, Class A, Mice, Presenilin-1, HEK293 Cells, Proteolysis
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