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Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies
Open accessAbstract
receptor 2 (apoER2), sortilin-related receptor (SorLA/ LR11), LRP5, and LRP6.These receptors have distinct physiological or pathophysiolgical roles, likely due to differences in their affinity to ligands, protein stability, endocytosis rate, signaling potency, cellular localization, and tissue expression pattern.While these receptors bind diverse extracellular ligands, some of them recognize key molecules in the pathogenesis of Alzheimer's disease (AD), such as apoE and amyloid- peptides (As) for cellular trafficking and/or signaling pathways.Given that the 4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for AD among the three human alleles (2, 3, and 4), the potential contributions of LDLR family members to AD development have attracted great interest by many laboratories around the world for over two decades (1, 2).Cumulative evidence from preclinical studies using cellular or animal studies indicates that LDLR family members can contribute to AD pathogenesis through modulating A accumulation or neurodegenerative processes.However, as there are currently no complete cellular or animal models that can recapitulate all pathological features of AD, parallel understanding between cellular/animal studies and human studies is necessary to define the specific role of any molecule in AD pathogenesis.Herein, among the LDLR family members, we comprehensively discuss the roles of LRP1 in AD pathogenesis by reviewing both preclinical studies using cellular/animal models, and clinical studies analyzing human samples/cohorts.We will specifically review current knowledge regarding: 1) LRP1 expression during AD progression, 2) contribution of Abstract Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years.Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid- peptides (As) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in A-independent manners.Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD.Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development.Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified.In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through A-dependent and -independent pathways by reviewing both clinical and preclinical studies.We also discuss potential therapeutic strategies for AD by targeting LRP1.-Shinohara,M., M. Tachibana, T. Kanekiyo, and G. Bu.Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies.
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“These pathways highlight how neuronal and glial interactions modulate microglial activity through Apoe, App, Trem2, and Lrp1 [Krasemann et al., 2017; Lin & Holtzman 2024; Shinohara et al., 2017].”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Shinohara et al., 2017
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“Lrp1 binds to Apoe-containing lipoproteins and facilitates the endocytosis and degradation of Aβ [Tachibana et al., 2019; Shinohara et al., 2017].”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Shinohara et al., 2017
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“Additionally, the Apoe-Lrp1 pathway is essential for lipid transport and Aβ clearance across the blood-brain barrier.”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Shinohara et al., 2017
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“has also been implicated in AD pathology. 21 , 32 , 33”
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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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RETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
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Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
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Research works printed but not linked: 1
- Kanekiyo, 2014, The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer's disease, Front. Aging Neurosci., 6, 93, 10.3389/fnagi.2014.00093 · DOI · Paper page
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LRP1 is a master regulator of tau uptake and spread
Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y. E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2156-5 · Cited by 541
ApoE4: an emerging therapeutic target for Alzheimer’s disease
Safieh, M., Korczyn, A. D., & Michaelson, D. M. (2019) · BMC Medicine · doi:10.1186/s12916-019-1299-4 · Cited by 449
Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies
Chew, H., Solomon, V. A., & Fonteh, A. N. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00598 · Cited by 353
Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease
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Metadata
- Authors
- Shinohara, M., Tachibana, M., Kanekiyo, T., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Shinohara, Mitsuru
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 58
- Issue
- 7
- Pages
- 1267-1281
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC5496044
- OpenAlex
- W2605039207
- Cited by
- 297
- References
- 184
- Citations by year
- 2026: 30 · 2025: 51 · 2024: 44 · 2023: 37 · 2022: 38 · 2021: 38 · 2020: 25 · 2019: 20 · 2018: 7 · 2017: 7
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- 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
- National Institutes of Health (P50AG016574, RF1AG051504, R01AG027924, R01AG035355, R01AG046205, P01NS074969)
- Cure Alzheimer’s Fund
- Naito Foundation
- BrightFocus Foundation
- 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 › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- LRP1, Alzheimer's disease, LDL receptor family, amyloid-beta metabolism, APOE ε4, late-onset Alzheimer's disease, amyloid-beta deposition, neuroinflammation, neurodegeneration, brain homeostasis, APOE ε4 carriers
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Humans, Biomarkers, Amyloid beta-Peptides, Low Density Lipoprotein Receptor-Related Protein-1, Molecular Targeted Therapy
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