A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance
Open accessAbstract
Amyloid-β (Aβ) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer9s disease (AD). The imbalance of Aβ production and clearance leads to Aβ accumulation and Aβ deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in Aβ clearance. We explored the role of low-density lipoprotein receptor-related protein 4 (LRP4), a member of the LDLR family, in AD pathology. We show that Lrp4 is specifically expressed in astrocytes and its levels in astrocytes were higher than those of Ldlr and Lrp1, both of which have been implicated in Aβ uptake. LRP4 was reduced in postmortem brain tissues of AD patients. Genetic deletion of the Lrp4 gene augmented Aβ plaques in 5xFAD male mice, an AD mouse model, and exacerbated the deficits in neurotransmission, synchrony between the hippocampus and PFC, and cognition. Mechanistically, LRP4 promotes Aβ uptake by astrocytes likely by interacting with ApoE. Together, our study demonstrates that astrocytic LRP4 plays an important role in Aβ pathology and cognitive function. SIGNIFICANCE STATEMENT This study investigates how astrocytes, a type of non-nerve cells in the brain, may contribute to Alzheimer9s disease (AD) development. We demonstrate that the low-density lipoprotein receptor-related protein 4 (LRP4) is reduced in the brain of AD patients. Mimicking the reduced levels in an AD mouse model exacerbates cognitive impairment and increases amyloid aggregates that are known to damage the brain. We show that LRP4 could promote the clearance of amyloid protein by astrocytes. Our results reveal a previously unappreciated role of LRP4 in AD development.
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LRP4 is the major ApoE receptor in astrocytes to promote Aβ clearance.
“we focused on LRP4, the major ApoE receptor in astrocytes, to promote Aβ clearance (43).”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [43]
The Results section says LRP4 in astrocytes promotes Aβ uptake by serving as an ApoE receptor. The Discussion says LRP4 levels are 4–10 times higher than those of LDLR and LRP1 and proposes that it may play a key role in uptake; it does not establish that LRP4 is the major ApoE receptor. Page numbers are unavailable in the indexed passages. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAmyloid pathology is exacerbated in 5×FAD mice lacking LRP4.
“amyloid pathology is exacerbated in 5×FAD mice lacking LRP4”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [43]
LRP4 is downregulated in the hippocampus, cortex, and entorhinal cortex of AD patients.
“LRP4 is downregulated in the hippocampus, cortex, and entorhinal cortex of AD patients”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [43]
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Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 4× · see citing works
“5xFAD transgenic mice (B6SJL-Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas/Mmja) were from The Jackson Laboratory (MMRRC stock #34 840-JAX) (Oakley et al., 2006), which express human APP and PSEN1 transgenes with five ADlinked mutations (the Swedish [K670N/M671L], Florida [I716V], and London [V717I]…”
BackgroundResultInfluentialNLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898 · see citing works
A gene expression atlas of the central nervous system based on bacterial artificial chromosomes
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., et al. (2003) · Nature · doi:10.1038/nature02033 · Cited by 2,108 · see citing works
The Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · see citing works
Normal aging induces A1-like astrocyte reactivity
Clarke, L. E., Liddelow, S. A., Chakraborty, C., Münch, A. E., Heiman, M., & Barres, B. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800165115 · Cited by 1,237 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · cited 2× · see citing works
“In mice, ApoE4 impairs Ab clearance without altering Ab production (Castellano et al., 2011).”
BackgroundLin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J. (1995) · Nature Medicine · doi:10.1038/nm1295-1291 · Cited by 592 · see citing works
Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R., et al. (2004) · Nature Medicine · doi:10.1038/nm1058 · Cited by 571 · see citing works
Neuronal Clearance of Amyloid-β by Endocytic Receptor LRP1
Kanekiyo, T., Cirrito, J. R., Liu, C.-C., Shinohara, M., Li, J., Schuler, D. R., Shinohara, M., Holtzman, D. M., & Bu, G. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3487-13.2013 · Cited by 280 · see citing works
Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · cited 1× · see citing works
“Lack of Ldlr aggravates Ab deposits in AD transgenic mice (Cao et al., 2006), whereas Ldlr overexpression reduces Ab deposition and increases Ab clearance (J. Kim et al., 2009).”
BackgroundAstrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition
Liu, C.-C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3442-16.2017 · Cited by 267 · see citing works
APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
Youmans, K. L., Tai, L. M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W. A., Estus, S., Rebeck, G. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407957 · Cited by 259 · cited 2× · see citing works
“Thioflavin S (Thio-S) staining for plaque and quantification were conducted as previously described (Wen et al., 2011; Youmans et al., 2012) by an investigator blind to the genotype beginning with the lateral-most section in the ROI, every sixth tissue section of six consecutive sections was used.”
MethodLin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.011 · Cited by 210 · see citing works
Lee, C. Y. D., Tse, W., Smith, J. D., & Landreth, G. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.295451 · Cited by 178 · see citing works
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · cited 3× · see citing works
“Third, Ab clearance is regulated by LDLR family members in particular LDLR and LRP1 (LDLR-related protein 1) (LaneDonovan et al., 2014; Lane-Donovan and Herz, 2017).”
BackgroundAmyloid-β-Induced Astrocytic Phagocytosis is Mediated by CD36, CD47 and RAGE
Jones, R. S., Minogue, A. M., Connor, T. J., & Lynch, M. A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9427-3 · Cited by 147 · cited 1× · see citing works
“…soluble and insoluble Ab (Wisniewski and Wegiel, 1991; Funato et al., 1998; Wyss-Coray et al., 2003; Nielsen et al., 2009; Chung et al., 2013; Jones et al., 2013; R. X. Liu et al., 2016) and degrade them via the late endolysosomal pathway (Shaffer et al., 1995; Wyss-Coray et al., 2003;…”
BackgroundThal, D. R., Schultz, C., Dehghani, F., Yamaguchi, H., Braak, H., & Braak, E. (2000) · Acta Neuropathologica · doi:10.1007/s004010000242 · Cited by 136 · see citing works
Lrp4 in astrocytes modulates glutamatergic transmission
Sun, X.-D., Li, L., Liu, F., Huang, Z.-H., Bean, J. C., Jiao, H.-F., Barik, A., Kim, S.-M., Wu, H., Shen, C., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4326 · Cited by 102 · cited 19× · see citing works
“Lrp4f/f (Wu et al., 2012), GFAP-Cre (Zhuo et al., 2001), Ai9 (Madisen et al., 2010), GFAP-CreERT2 (Casper et al., 2007), Neurod6-Cre (Goebbels et al., 2006), Thy1GFP (Feng et al., 2000), and Slc1a2-EGFP (Gong et al., 2003) were as described previously (Sun et al., 2016).”
BackgroundMethodResultInfluentialSelf-citationIstradefylline reduces memory deficits in aging mice with amyloid pathology
Orr, A. G., Lo, I., Schumacher, H., Ho, K., Gill, M., Guo, W., Kim, D. H., Knox, A., Saito, T., Saido, T. C., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.10.014 · Cited by 87 · see citing works
Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4
Gomez, A. M., Froemke, R. C., & Burden, S. J. (2014) · eLife · doi:10.7554/elife.04287 · Cited by 47 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apoli- poprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923.
- Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993a) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977-1981.
- Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993b) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:8098-8102.
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Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes
Komai, M., Noda, Y., Ikeda, A., Kaneshiro, N., Kamikubo, Y., Sakurai, T., Uehara, T., & Takasugi, N. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100510 · Cited by 13 · see citing works
Kurgan, N., Stoikos, J., Baranowski, B. J., Yumol, J., Dhaliwal, R., Sweezey-Munroe, J. B., Fajardo, V. A., Gittings, W., Macpherson, R. E. K., & Klentrou, P. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4768 · Cited by 12 · see citing works
- Authors
- Zhang, H., Chen, W., Tan, Z., Zhang, L., Dong, Z., Cui, W., Zhao, K., Wang, H., Jing, H., Cao, R., Kim, C., Safar, J. G., Xiong, W.-C., & Mei, L.
- Affiliations
- Case Western Reserve University (US)
- Louis Stokes Cleveland VA Medical Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-05-26
- Volume
- 40
- Issue
- 28
- Pages
- 5347-5361
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7343327
- OpenAlex
- W3028888328
- Cited by
- 58
- References
- 26
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 12 · 2023: 11 · 2022: 8 · 2021: 10 · 2020: 2
- FWCI
- 4.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (RF1AG058267, RF1AG051510, R01AG051510, RF1AG066526, RF1AG061797)
- National Institute of Mental Health (R01MH083317)
- National Institute of Neurological Disorders and Stroke (R01NS090083, R01NS082007)
- Topics
- Health Sciences › Medicine › Physiology › 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
- LRP4, amyloid-beta clearance, astrocytes, Alzheimer's disease, amyloid plaques, apolipoprotein E, LDL receptor, LRP1, 5xFAD mice, cognitive impairment, amyloid-beta uptake
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, Female, Humans, Male, Amyloid beta-Peptides, LDL-Receptor Related Proteins, Mice, Plaque, Amyloid
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