The Low Density Lipoprotein Receptor Regulates the Level of CentralNervous System Human and Murine Apolipoprotein E but Does Not Modify AmyloidPlaque Pathology in PDAPPMice
Open accessAbstract
Apolipoprotein E (apoE), a chaperone for the amyloid beta (Abeta) peptide, regulates the deposition and structure of Abeta that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown. We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE. Cells lacking LDLR were unable to appreciably endocytose astrocyte-secreted apoE-containing lipoprotein particles. Moreover, cells overexpressing LDLR showed a dramatic increase in apoE endocytosis and degradation. We also found that LDLR knock-out (Ldlr-/-) mice had a significant, approximately 50% increase in the level of apoE in the cerebrospinal fluid and extracellular pools of the brain. However, when the PDAPP mouse model of AD was bred onto an Ldlr-/- background, we did not observe a significant change in brain Abeta levels either before or after the onset of Abeta deposition. Interestingly, human APOE3 or APOE4 (but not APOE2) knock-in mice bred on an Ldlr-/- background had a 210% and 380% increase, respectively, in the level of apoE in cerebrospinal fluid. These results demonstrate that central nervous system levels of both human and murine apoE are directly regulated by LDLR. Although the increase in murine apoE caused by LDLR deficiency was not sufficient to affect Abeta levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoE3 and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD.
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Several groups have reported that the concentration of apoE in the brains of human apoE knock-in mice varies in an apoE isoform-dependent manner, with E2 > E3 > E4.
“Although there are some conflicting studies (61), several groups have reported that the concentration of apoE in the brains of human apoE knock-in mice varies in an apoE isoform-dependent manner, that is, E2>E3>E4 (14, 62, 63).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [62]
Figure 6 and the Results (page unavailable) report apoE levels in the cerebrospinal fluid of human APOE knock-in mice: E2 was significantly higher than E3 and E4, and the reported E3 value was numerically higher than E4. The paper does not establish that apoE concentration in brain tissue follows this ranking, or report a significant E3-versus-E4 difference. (LLM, conf=0.86)
Experimental — accuracy not yet measuredKnockout mouse studies have provided direct evidence for LDLR and LRP1 as major apoE receptors in the brain.
“Knockout mouse studies have provided direct evidence for LDLR and LRP1 as major apoE receptors in the brain (Elder et al., 2007; Fryer et al., 2005; Liu et al., 2007).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Fryer et al., 2005
The Results report increased brain extracellular and CSF apoE in LDLR-knockout mice, supporting LDLR as an important brain apoE receptor. The Discussion says the effect of LRP on brain apoE levels is difficult to assess because LRP-knockout mice die early in embryonic development; this paper therefore does not provide comparable direct knockout-mouse evidence for LRP1. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInactivation of Ldlr or Lrp1 increases, whereas overexpression of LDLR decreases, ApoE protein in the brain.
“Inactivation of the Ldlr or Lrp1 gene increases, whereas overexpression of LDLR decreases, ApoE protein in the brain (19, 35–37).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [36]
The Results (page not provided) report that Ldlr knockout increased apoE in mouse CSF and cortical tissue. The paper does not establish that Lrp1 inactivation increases brain apoE; the Discussion says its effect was difficult to assess. LDLR overexpression increased apoE uptake and degradation in cultured cells, but the paper does not report that it decreased brain apoE protein. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDeletion of either LDLR or LRP1 significantly increases apoE levels in brain.
“deletion of either LDLR or LRP1 significantly increases apoE levels in brain”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Fryer et al 2005
The Results (page not supplied) report significantly increased brain cortical apoE in LDLR-knockout mice. The Discussion (page not supplied) says LRP-knockout mice die early in embryonic development, making LRP's effect on brain apoE levels difficult to assess; it does not establish the claimed increase after LRP1 deletion. (LLM, conf=0.90)
Experimental — accuracy not yet measuredLDLR is one of the major apoE endocytic receptors in the brain.
“Since LDLR is one of the major apoE endocytic receptors in the brain (Fryer et al., 2005), we expected that LDLR overexpression would lead to a reduction in apoE protein levels through enhanced receptor-mediated endocytosis.”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Fryer et al., 2005
LDLR deficiency does not alter brain cholesterol levels.
“Although LDLR deficiency significantly increased murine brain apoE levels by ~50%, it did not alter brain cholesterol levels (Elder et al., 2007; Fryer et al., 2005; Quan et al., 2003; Taha et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Fryer et al., 2005
LDLR deficiency significantly increases murine brain apoE levels by approximately 50%.
“Although LDLR deficiency significantly increased murine brain apoE levels by ~50%, it did not alter brain cholesterol levels (Elder et al., 2007; Fryer et al., 2005; Quan et al., 2003; Taha et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Fryer et al., 2005
In PDAPP transgenic mice on a LDLR-deficient background, there was no significant change in brain Aβ levels both before and after the onset of amyloid deposition.
“Previously, we demonstrated that there was no significant change in brain Aβ levels both before and after the onset of amyloid deposition in PDAPP transgenic mice on a LDLR-deficient background (Fryer et al., 2005).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Fryer et al., 2005
Deletion of Ldlr increases APOE levels in the brain.
“Indeed, deletion of Ldlr increased APOE levels in the brain. 59 , 60 , 61”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [59]
LDLR is one of the major APOE receptors in the brain and facilitates the endocytosis of APOE-bound lipoprotein particles.
“LDLR is one of the major APOE receptors in the brain and facilitates the endocytosis of APOE‐bound lipoprotein particles. 59”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [59]
LDLR is an APOE receptor responsible for APOE uptake.
“As LDLR is an APOE receptor responsible for APOE uptake, we also measured the levels of APOE in the brain.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [59]
Ldlr is a major receptor for the reuptake of ApoE lipoproteins.
“Ldlr is a major receptor for the reuptake of ApoE lipoproteins (61).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [61]
LDLR is a key receptor for lipidated ApoE (lipApoE) in the brain.
“While this feature may relate to type III hyperlipoproteinemia observed in 1–10% of APOE2 homozygotes22, it has been underappreciated as a potential protective mechanism for LOAD, despite the fact LDLR is a key receptor for lipidated ApoE (lipApoE) in the brain23.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [23]
LipApoE2 minimally engages LDLR in the brain.
“suggesting lipApoE2 minimally engages LDLR in the brain, consistent with Ldlr KO mouse studies23.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [23]
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“3,4 Because LDLR is a major endocytic APOE receptor, 59 it was hypothesized that modulating LDLR levels could influence brain APOE levels.”
- Authors
- 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., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Eli Lilly (United States) (US)
- Pediatrics and Genetics (US)
- Duke University (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 280
- Issue
- 27
- Pages
- 25754-25759
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2145017801
- Cited by
- 139
- References
- 10
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 9 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 9 · 2013: 3 · 2012: 12
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- MetLife Foundation
- Eli Lilly and Company
- National Institutes of Health (AG05681, AG13956, AG11355)
- National Institute on Aging (AG11355, P 50 AG05681, P50AG005681, AG13956, P01AG011355)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, LDL receptor, Alzheimer's disease, amyloid-beta, amyloid plaques, PDAPP mice, APOE3, APOE ε4, apoE receptors, lipoprotein uptake
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Endocytosis, Humans, Mice, Inbred C57BL, Receptors, LDL, Amyloid beta-Protein Precursor, Mice, Knockout, Mice
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