Low-density Lipoprotein Receptor Represents an Apolipoprotein E-independent Pathway of Aβ Uptake and Degradation by Astrocytes
Open accessAbstract
Accumulation of the amyloid β (Aβ) peptide within the brain is hypothesized to be one of the main causes underlying the pathogenic events that occur in Alzheimer disease (AD). Consequently, identifying pathways by which Aβ is cleared from the brain is crucial for better understanding of the disease pathogenesis and developing novel therapeutics. Cellular uptake and degradation by glial cells is one means by which Aβ may be cleared from the brain. In the current study, we demonstrate that modulating levels of the low-density lipoprotein receptor (LDLR), a cell surface receptor that regulates the amount of apolipoprotein E (apoE) in the brain, altered both the uptake and degradation of Aβ by astrocytes. Deletion of LDLR caused a decrease in Aβ uptake, whereas increasing LDLR levels significantly enhanced both the uptake and clearance of Aβ. Increasing LDLR levels also enhanced the cellular degradation of Aβ and facilitated the vesicular transport of Aβ to lysosomes. Despite the fact that LDLR regulated the uptake of apoE by astrocytes, we found that the effect of LDLR on Aβ uptake and clearance occurred in the absence of apoE. Finally, we provide evidence that Aβ can directly bind to LDLR, suggesting that an interaction between LDLR and Aβ could be responsible for LDLR-mediated Aβ uptake. Therefore, these results identify LDLR as a receptor that mediates Aβ uptake and clearance by astrocytes, and provide evidence that increasing glial LDLR levels may promote Aβ degradation within the brain.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LDLR regulates Aβ uptake and clearance even in the absence of APOE, indicating APOE-independent effects.
“Indeed, LDLR has been demonstrated to regulate Aβ uptake and clearance even in the absence of APOE, indicating APOE‐independent effects.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [76]
The bulk of soluble Aβ is cleared through its direct interaction with the LDL receptor family expressed by brain capillary endothelium, neurons, and astrocytes.
“Several studies have shown that the bulk of soluble Aβ is cleared through its direct interaction with the LDL receptor family expressed by brain capillary endothelium [37], neurons [24,38], and astrocytes [39,40], therefore pharmacological disruption of the apoE/Aβ binding is unlikely to impair this process.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [39]
Both LDLR and LRP1 directly interact with amyloid β even in the absence of ApoE.
“both receptors also directly interact with amyloid β even in the absence of ApoE [17].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [17]
The protective effect of LDLR up-regulation can be related to the receptor subtype and/or its overexpression in nonneuronal cells capable of efficient Aβ degradation.
“These mice overexpress LDLR in neurons and astrocytes, which indicates that the protective effect of LDLR up-regulation can be related to the receptor subtype and/or its overexpression in nonneuronal cells capable of efficient Ab degradation.42”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [42]
LDLR has important roles in modulating AD pathologies, in part via uptake and clearance of Aβ by astrocytes.
“important roles were shown for LDLR in modulating AD pathologies57–59, in part via uptake and clearance of Aβ by astrocytes60.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [60]
LDLR is a lipoprotein receptor shown to bind APOE and Aβ, and regulate Aβ phagocytosis in astrocytes.
“a lipoprotein receptor shown to bind APOE and Aβ, and regulate Aβ phagocytosis in astrocytes74.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [74]
APOE-KO iAstrocytes take up Aβ42 probably through direct lipoprotein receptor uptake of Aβ42.
“probably through direct lipoprotein receptor uptake of Aβ42 (Basak et al., 2012).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Basak et al., 2012
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703 · see citing works
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028 · see citing works
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280 · see citing works
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Self-citationReceptor-Mediated Endocytosis: Concepts Emerging from the LDL Receptor System
Goldstein, J. L., Brown, M. S., Anderson, R. G. W., Russell, D. W., & Schneider, W. J. (1985) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.01.110185.000245 · Cited by 1,600 · see citing works
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
Self-citationStrittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · 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 · see citing works
Self-citationRelationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · see citing works
Adult mouse astrocytes degrade amyloid-β in vitro and in situ
Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., & Husemann, J. (2003) · Nature Medicine · doi:10.1038/nm838 · Cited by 909 · 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
Self-citationApolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · see citing works
Self-citationLack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · see citing works
LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms
Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H. W., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.017 · Cited by 828 · see citing works
apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · see citing works
Self-citationThe role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701 · 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
Wileman, T. E., Harding, C., & Stahl, P. D. (1985) · Biochemical Journal · doi:10.1042/bj2320001 · Cited by 566 · see citing works
Clearing the brain's amyloid cobwebs
Selkoe, D. J. (2001) · Neuron · doi:10.1016/s0896-6273(01)00475-5 · Cited by 541 · see citing works
Isoform-specific binding of apolipoprotein E to beta-amyloid.
LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31529-6 · Cited by 540 · see citing works
Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15233 · Cited by 486 · see citing works
A Hundred Years of Alzheimer's Disease Research
Hardy, J. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.016 · Cited by 467 · see citing works
ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459 · see citing works
Self-citationLipoprotein receptors in the nervous system
Herz, J., & Bock, H. H. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.110601.135342 · Cited by 457 · see citing works
Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process
De Strooper, B. (2010) · Physiological Reviews · doi:10.1152/physrev.00023.2009 · Cited by 455 · see citing works
Clearance of Alzheimer's Aβ Peptide
Tanzi, R. E., Moir, R. D., & Wagner, S. L. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.024 · Cited by 431 · see citing works
Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains
Nagele, R. G., D’Andrea, M. R., Lee, H., Venkataraman, V., & Wang, H.-Y. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02361-8 · Cited by 416 · see citing works
Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
Mandrekar, S., Jiang, Q., Lee, C. Y. D., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5572-08.2009 · Cited by 415 · see citing works
Self-citationMatrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism
Yin, K.-J., Cirrito, J. R., Yan, P., Hu, X., Xiao, Q., Pan, X., Bateman, R., Song, H., Hsu, F.-F., Turk, J., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2085-06.2006 · Cited by 381 · see citing works
Self-citationKim, 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 · see citing works
Self-citationTOKUDA, T., CALERO, M., MATSUBARA, E., VIDAL, R., KUMAR, A., PERMANNE, B., ZLOKOVIC, B., SMITH, J. D., LADU, M. J., ROSTAGNO, A., et al. (2000) · Biochemical Journal · doi:10.1042/bj3480359 · Cited by 272 · see citing works
Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30001 · Cited by 222 · see citing works
Self-citationKanekiyo, T., Zhang, J., Liu, Q., Liu, C.-C., Zhang, L., & Bu, G. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5491-10.2011 · Cited by 212 · see citing works
Early association of reactive astrocytes with senile plaques in Alzheimer's disease
Pike, C. J., Cummings, B. J., & Cotman, C. W. (1995) · Experimental Neurology · doi:10.1016/0014-4886(95)90022-5 · Cited by 199 · see citing works
Dunn, K., & Maxfield, F. R. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.117.2.301 · Cited by 195 · see citing works
Amyloid β protein (Aβ) removal by neuroglial cells in culture
Shaffer, L. M., Dority, M. D., Gupta‐Bansal, R., Frederickson, R. C. A., Younkin, S. G., & Brunden, K. R. (1995) · Neurobiology of Aging · doi:10.1016/0197-4580(95)00055-j · Cited by 180 · see citing works
(1998) · Europe PMC (PubMed Central) · Cited by 146 · see citing works
Fryer, J. D., DeMattos, R. B., McCormick, L. M., O'Dell, M. A., Spinner, M. L., Bales, K. R., Paul, S. M., Sullivan, P. M., Parsadanian, M., Bu, G., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502143200 · Cited by 139 · see citing works
Self-citationThal, 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
Yamada, K., Hashimoto, T., Yabuki, C., Nagae, Y., Tachikawa, M., Strickland, D. K., Liu, Q., Bu, G., Basak, J. M., Holtzman, D. M., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801487200 · Cited by 119 · see citing works
Self-citationInternalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E
Saavedra, L., Mohamed, A., Ma, V., Kar, S., & de Chaves, E. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701823200 · Cited by 118 · see citing works
Astrocytes and the plaques of Alzheimer's disease
Mandybur, T. I., & Chuirazzi, C. C. (1990) · Neurology · doi:10.1212/wnl.40.4.635 · Cited by 111 · see citing works
Clearance of Alzheimer's Aβ PeptideThe Many Roads to Perdition
Tanzi, R. E., Moir, R. D., & Wagner, S. L. (2004) · Neuron · doi:10.1016/s0896-6273(04)00533-1 · Cited by 107 · see citing works
Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice
Cao, D., Fukuchi, K.-I., Wan, H., Kim, H., & Li, L. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.011 · Cited by 106 · see citing works
Binding and uptake of Aβ1‐42 by primary human astrocytes <i>in vitro</i>
Nielsen, H. M., Veerhuis, R., Holmqvist, B., & Janciauskiene, S. (2009) · Glia · doi:10.1002/glia.20822 · Cited by 96 · see citing works
Katsouri, L., & Georgopoulos, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021880 · Cited by 72 · see citing works
Li, M., Husic, N., Lin, Y., Christensen, H. M., Malik, I., McIver, S. R., Daniels, C. M. L., Harris, D. A., Kotzbauer, P. T., Goldberg, M. P., et al. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.03.019 · Cited by 61 · see citing works
Receptor-associated Protein Interacts with Amyloid-β Peptide and Promotes Its Cellular Uptake
Kanekiyo, T., & Bu, G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.015032 · Cited by 54 · see citing works
Elder, G. A., Cho, J. Y., English, D. F., Franciosi, S., Schmeidler, J., Sosa, M. A. G., Gasperi, R. D., Fisher, E. A., Mathews, P. M., Haroutunian, V., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04614.x · Cited by 26 · see citing works
Thal, D. R., Härtig, W., & Schober, R. (1999) · PubMed · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Self-citationApolipoprotein 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 · see citing works
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · 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
Yanamandra, K., Kfoury, N., Jiang, H., Mahan, T. E., Ma, S., Maloney, S. E., Wozniak, D. F., Diamond, M. I., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.046 · Cited by 574 · see citing works
Self-citationVerghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
Self-citationApolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · see citing works
Kanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281 · see citing works
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading
Martini-Stoica, H., Cole, A. L., Swartzlander, D. B., Chen, F., Wan, Y.-W., Bajaj, L., Bader, D. A., Lee, V. M. Y., Trojanowski, J. Q., Liu, Z., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20172158 · Cited by 253 · 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 · see citing works
Self-citationAmyloid-β Receptors: The Good, the Bad, and the Prion Protein
Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V., & Hooper, N. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.702704 · Cited by 256 · see citing works
Garwood, C. J., Ratcliffe, L. E., Simpson, J. E., Heath, P. R., Ince, P. G., & Wharton, S. B. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12338 · Cited by 233 · see citing works
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210 · see citing works
Self-citationApolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease
Liao, F., Yoon, H., & Kim, J. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000383 · Cited by 191 · see citing works
Self-citationAstrocyte Senescence and Alzheimer’s Disease: A Review
Han, X., Zhang, T., Liu, H., Mi, Y., & Gou, X. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00148 · Cited by 177 · see citing works
Tai, L. M., Bilousova, T., Jungbauer, L., Roeske, S. K., Youmans, K. L., Yu, C., Poon, W. W., Cornwell, L. B., Miller, C. A., Vinters, H. V., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.442103 · Cited by 165 · see citing works
Castellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · see citing works
Self-citationChandra, S., Jana, M., & Pahan, K. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0054-18.2018 · Cited by 134 · see citing works
Avila-Muñoz, E., & Arias, C. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.07.004 · Cited by 114 · see citing works
Functional Roles of the Interaction of APP and Lipoprotein Receptors
Pohlkamp, T., Wasser, C. R., & Herz, J. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00054 · Cited by 92 · see citing works
Astrocyte–neuron interplay in maladaptive plasticity.
Papa, M., De Luca, C., Petta, F., Alberghina, L., & Cirillo, G. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.010 · Cited by 104 · see citing works
de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105 · see citing works
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“60 Therefore, reduced LDLR binding of ApoE2 may free up LDLR for binding and clearance of other ligands, including A b , thus decreasing amyloid pathology.”
Self-citationKuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.034 · Cited by 89 · see citing works
“These mice overexpress LDLR in neurons and astrocytes, which indicates that the protective effect of LDLR up-regulation can be related to the receptor subtype and/or its overexpression in nonneuronal cells capable of efficient Ab degradation.(42) In addition, treatment of several AD Tg mice models with liver X recepto…”
BackgroundSelf-citationHan, S.-H., Park, J.-C., & Mook-Jung, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.004 · Cited by 67 · see citing works
Activation of PPARα enhances astroglial uptake and degradation of β-amyloid
Raha, S., Ghosh, A., Dutta, D., Patel, D. R., & Pahan, K. (2021) · Science Signaling · doi:10.1126/scisignal.abg4747 · Cited by 63 · see citing works
Chandra, S., Di Meco, A., Dodiya, H. B., Popovic, J., Cuddy, L. K., Weigle, I. Q., Zhang, X., Sadleir, K., Sisodia, S. S., & Vassar, R. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00635-2 · Cited by 58 · see citing works
Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0075-0 · Cited by 57 · see citing works
Self-citationChoi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1904 · Cited by 49 · see citing works
Self-citationMatsumoto, K., Chiba, Y., Fujihara, R., Kubo, H., Sakamoto, H., & Ueno, M. (2015) · Histochemistry and Cell Biology · doi:10.1007/s00418-015-1366-7 · Cited by 46 · see citing works
Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44 · see citing works
Li, G., Kim, C., Kim, J., Yoon, H., Zhou, H., & Kim, J. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150024 · Cited by 39 · see citing works
Self-citationAPOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease
Brookhouser, N., Raman, S., Frisch, C., Srinivasan, G., & Brafman, D. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01076-3 · Cited by 33 · see citing works
ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology
Cao, Y., Xu, H., Zhu, Y., Shi, M.-J., Wei, L., Zhang, J., Cheng, S., Shi, Y., Tong, H., Kang, L., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000313 · Cited by 31 · see citing works
RetractedKarahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2 · see citing works
“76 Furthermore,both Ldlr KOand Ldlr-Apoe double KO 5XFAD mice showed reduced astrogliosis and microgliosis, whereas Apoe KO mice did not.”
Self-citation
- Authors
- Basak, J. M., Verghese, P. B., Yoon, H., Kim, J., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 287
- Issue
- 17
- Pages
- 13959-13971
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3340151
- OpenAlex
- W2026723397
- Semantic Scholar
- dd37983d083fd9ddcad04355c3392525f013f432
- Cited by
- 192
- References
- 52
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 8 · 2023: 9 · 2022: 15 · 2021: 18 · 2020: 14 · 2019: 14 · 2018: 13 · 2017: 9 · 2016: 14 · 2015: 15 · 2014: 29 · 2013: 4 · 2012: 5
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (5p30ns069329-02)
- National Institute on Aging (R01 AG013956, R37AG013956, AG13956)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, NS034467, R37NS034467, P30 NS057105, R01NS034467)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- LDL receptor, amyloid-beta, astrocytes, apolipoprotein E, amyloid clearance, amyloid degradation, lysosomal trafficking, ligand-receptor interactions, Alzheimer's disease, glial cells
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Lysosomes, Mice, Transgenic, Models, Biological, Protein Binding, Receptors, LDL, Amyloid beta-Peptides, Protein Isoforms, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
