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Cited by 281Alzheimer's disease research and treatmentsBarrier Structure and Function StudiesNeuroinflammation and Neurodegeneration Mechanisms

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The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease

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Kanekiyo, Takahisa, Bu, Guojun·2014·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2014.00093PMC PMC4033011
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Abstract

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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FIGURE 1 LRP1-mediated Aβ clearance pathways. Aβ is predominantly generated in neurons and secreted into ISF. Proteolytic degradation by endopeptidases (e.g., neprilysin, insulin-degrading enzyme) comprises a major Aβ clearance pathway. Cellular Aβ clearance also plays a critical role in eliminating Aβ from the brain, where LRP1 significantly regulates its endocytosis and subsequent lysosomal degradation. LRP1 is expressed in several different brain cell types, including neurons, astrocytes, microglia, endothelial cells, and vascular mural cells (vascular smooth muscle cells and pericytes). In brain parenchyma, neurons, astrocytes, and microglia can take up and degrade Aβ mainly in lysosomes. ISF is drained along the cerebrovasculature, where Aβ is degraded by vascular cells. A portion of Aβ may be transported out of the brain through the BBB. Disturbances of these pathways induce Aβ accumulation and deposition as amyloid plaques in brain parenchyma, perivascular regions as CAA and sometimes also inside neurons and intraneuronal Aβ.
FIGURE 1 LRP1-mediated Aβ clearance pathways. Aβ is predominantly generated in neurons and secreted into ISF. Proteolytic degradation by endopeptidases (e.g., neprilysin, insulin-degrading enzyme) comprises a major Aβ clearance pathway. Cellular Aβ clearance also plays a critical role in eliminating Aβ from the brain, where LRP1 significantly regulates its endocytosis and subsequent lysosomal degradation. LRP1 is expressed in several different brain cell types, including neurons, astrocytes, microglia, endothelial cells, and vascular mural cells (vascular smooth muscle cells and pericytes). In brain parenchyma, neurons, astrocytes, and microglia can take up and degrade Aβ mainly in lysosomes. ISF is drained along the cerebrovasculature, where Aβ is degraded by vascular cells. A portion of Aβ may be transported out of the brain through the BBB. Disturbances of these pathways induce Aβ accumulation and deposition as amyloid plaques in brain parenchyma, perivascular regions as CAA and sometimes also inside neurons and intraneuronal Aβ.CC BY · PubMed Central
FIGURE 2 Possible pathways for LRP1-mediated Aβ uptake. LRP1 regulates Aβ internalization on the cell surface through several possible endocytic pathways: (1) Aβ binds to LRP1 directly for endocytosis through clathrin-dependent pathways; (2) Aβ binds to alternative cell surface receptors such as HSPG and PrPc with LRP1 directly or indirectly regulating Aβ endocytosis in a clathrin- or caveolin-dependent manner; (3) LRP1 may affect RhoA-mediated endocytic pathway for cellular Aβ uptake by regulating signal transduction pathways; (4) LRP1 controls the cytoskeleton architectures by modifying PI3K and/or FAK pathways, which may influence macropinocytosis or phagocytosis of Aβ in specific cell types. The majority of endocytosed Aβ traffics to lysosomes for subsequent degradation, whereas a small amount of Aβ can be recycled. Under some conditions, Aβ is likely to be exocytosed from the late endosomes/multi-vesicular body, which may induce propagation of Aβ aggregates. When Aβ accumulation overwhelms the capacity of lysosomes for degradation, Aβ aggregation may be induced in lysosomes.
FIGURE 2 Possible pathways for LRP1-mediated Aβ uptake. LRP1 regulates Aβ internalization on the cell surface through several possible endocytic pathways: (1) Aβ binds to LRP1 directly for endocytosis through clathrin-dependent pathways; (2) Aβ binds to alternative cell surface receptors such as HSPG and PrPc with LRP1 directly or indirectly regulating Aβ endocytosis in a clathrin- or caveolin-dependent manner; (3) LRP1 may affect RhoA-mediated endocytic pathway for cellular Aβ uptake by regulating signal transduction pathways; (4) LRP1 controls the cytoskeleton architectures by modifying PI3K and/or FAK pathways, which may influence macropinocytosis or phagocytosis of Aβ in specific cell types. The majority of endocytosed Aβ traffics to lysosomes for subsequent degradation, whereas a small amount of Aβ can be recycled. Under some conditions, Aβ is likely to be exocytosed from the late endosomes/multi-vesicular body, which may induce propagation of Aβ aggregates. When Aβ accumulation overwhelms the capacity of lysosomes for degradation, Aβ aggregation may be induced in lysosomes.CC BY · PubMed Central

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Metadata

Authors
Kanekiyo, T., & Bu, G.
Affiliations
Mayo Clinic (US)
Corresponding author
Kanekiyo, Takahisa
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2014-05-20
Volume
6
Pages
93-93
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2014.00093
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
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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