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Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition
Open accessAbstract
Accumulation and deposition of amyloid-β (Aβ) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). Aβ accumulation leads to the formation of Aβ aggregates, which may directly and indirectly lead to eventual neurodegeneration. While Aβ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Aβ is more evident in late-onset AD. To uncover the mechanisms underlying impaired Aβ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain Aβ metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain Aβ clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular Aβ uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several major Aβ-degrading enzymes, including matrix metalloproteases MMP2, MMP9, and insulin-degrading enzyme. More important, conditional knock-out of the Lrp1 gene in astrocytes in the background of APP/PS1 mice impaired brain Aβ clearance, exacerbated Aβ accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocytic LRP1 plays an important role in Aβ metabolism and that restoring LRP1 expression and function in the brain could be an effective strategy to facilitate Aβ clearance and counter amyloid pathology in AD. SIGNIFICANCE STATEMENT Astrocytes represent a major cell type regulating brain homeostasis; however, their roles in brain clearance of amyloid-β (Aβ) and underlying mechanism are not clear. In this study, we used both cellular models and conditional knock-out mouse models to address the role of a critical Aβ receptor, the low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. We found that LRP1 in astrocytes plays a critical role in brain Aβ clearance by modulating several Aβ-degrading enzymes and cellular degradation pathways. Our results establish a critical role of astrocytic LRP1 in brain Aβ clearance and shed light on specific Aβ clearance pathways that may help to establish new targets for AD prevention and therapy.
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“This family of receptors have essential roles in lipid and cholesterol transport, with LRP1 also implicated in the astrocytic uptake and degradation of amyloid-β [106-108].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [107]
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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“which has been implicated in the uptake and degradation of amyloid-β and tau [107, 147].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [107]
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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“Clearance of Aβ through direct association with ApoE or through binding to ApoE receptors decreases amyloid pathology in mouse models.”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [87]
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“However, LDLR, LRP1 and ApoER2 receptors are also present in astrocytes [15,24,63] and have been also shown to be involved in the Aβ clearance mediated by astrocytes [50,64].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [64]
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“Furthermore, receptors that bind to apoE have been shown to influence amyloid pathology. 21 , 41”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [41]
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“has also been implicated in AD pathology. 21 , 32 , 33”
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“LRP1 is a widely expressed receptor that was previously shown to enhance Aβ uptake, clearance, and degradation. 21”
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“Similarly, knockout of LRP1 in astrocytes decreases Aβ clearance and increases Aβ pathology [85, 87].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [87]
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“astrocytic LDLR and LRP1 have been shown to be involved in Aβ uptake and clearance, as confirmed by the significant change in Aβ accumulation observed in experimental models characterized by the knockdown or the overexpression of one of these two receptors [50,64,76]”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [64]
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“Cellular receptors such as low-density lipoprotein receptor-related protein 1 (LRP1) [47–50], LRP8 [51], LDLR [52] or RAGE [53] may also affect APP metabolism by either modulating the activities of β- and γ-secretase and/or directly Aβ levels through endocytosis.”
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In the citing paper
“Interestingly, Apoe-deficient astrocytes upregulate genes associated with inhibition of Aβ fibrillization (Ptgds and Cst3) and regulation of protein degradation (Ubb, Ubc and Ctsl) (Apelt et al, 2003; Davis et al, 2021; Liu et al, 2017a; Wegiel et al, 2000).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Liu et al, 2017a
Experimental — accuracy not yet measuredIn the citing paper
“AD is accompanied by activation of microglia and astrocytes1,2 that affects the clearance and production of Aβ42,3,4 development and propagation of tau pathology,5 exacerbates neurodegeneration, and influences disease progression and severity.6,7”
From CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease (2018) · cites this paper as [4]
In the citing paper
“the low‐density lipoprotein receptor‐related protein 1 (LRP1) plays an important role in Aβ degradation and transport across the blood–brain barrier (Kanekiyo et al., 2011, 2013; Liu et al., 2017; Ma et al., 2018; Shibata et al., 2000; Storck et al., 2016)”
From Alzheimer's amyloid‐β and tau protein accumulation is associated with decreased expression of the LDL receptor‐associated protein in human brain tissue (2020) · cites this paper as Liu et al., 2017
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Citations
Cites
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Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
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Lentivirus-delivered stable gene silencing by RNAi in primary cells.
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Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Self-citationAPOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Self-citationInflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532
Metadata
- Authors
- Liu, C.-C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-03-08
- Volume
- 37
- Issue
- 15
- Pages
- 4023-4031
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5391682
- OpenAlex
- W2593036876
- Cited by
- 267
- References
- 75
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 27 · 2023: 32 · 2022: 29 · 2021: 32 · 2020: 36 · 2019: 26 · 2018: 13 · 2017: 10
- FWCI
- 17.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- American Heart Association (15SDG22460003)
- National Institutes of Health
- National Institute on Aging (RF1AG051504, R01AG027924, RF1AG046205, R01AG046205, R01AG035355, P50AG016574)
- 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 › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- LRP1, astrocytes, amyloid-beta clearance, Alzheimer's disease, amyloid deposition, amyloid plaques, matrix metalloproteinases, insulin-degrading enzyme, APP/PS1 mice, conditional knockout
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Female, Humans, Male, Peptide Fragments, Receptors, LDL, Amyloid beta-Peptides, Mice, Knockout, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Plaque, Amyloid
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