Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model
Open accessAbstract
BACKGROUND: Apolipoprotein E (ApoE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer's disease (AD). The low-density lipoprotein receptor (LDLR) regulates ApoE levels in the periphery and in the central nervous system. LDLR has been identified on astrocytes and a number of studies show that it modulates amyloid deposition in AD transgenic mice. However these findings are controversial on whether LDLR deletion is beneficial or detrimental on the AD-like phenotype of the transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of LDLR in the development of the amyloid related phenotype we used an APP/PS1 transgenic mouse (5XFAD) that develops an AD-like pathology with amyloid plaques, astrocytosis and microgliosis. We found that 4 months old 5XFAD transgenic mice on the LDLR deficient background (LDLR-/-) have increased amyloid plaque deposition. This increase is associated with a significant decrease in astrocytosis and microgliosis in the 5XFAD/LDLR-/- mice. To further elucidate the role of LDLR in relation with ApoE we have generated 5XFAD transgenic mice on the ApoE deficient (ApoE-/-) or the ApoE/LDLR double deficient background (ApoE-/-/LDLR -/-). We have found that ApoE deletion in the 4 months old 5XFAD/ApoE-/- mice decreases amyloid plaque formation as expected, but has no effect on astrocytosis or microgliosis. By comparison 5XFAD/ApoE-/-LDLR -/- double deficient mice of the same age have increased amyloid deposition with decreased astrocytosis and microgliosis. CONCLUSIONS: Our analysis shows that LDL deficiency regulates astrocytosis and microgliosis in an AD mouse model. This effect is independent of ApoE, as both 5XFAD/LDLR -/- and 5XFAD/ApoE-/- LDLR -/- mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice. These results demonstrate that LDLR regulates glial response in this mouse model independently of ApoE and modifies amyloid deposition.
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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 [61]
Both Ldlr KO and Ldlr-Apoe double KO 5XFAD mice showed reduced astrogliosis and microgliosis, whereas Apoe KO mice did not.
“Furthermore, both Ldlr KO and Ldlr‐Apoe double KO 5XFAD mice showed reduced astrogliosis and microgliosis, whereas Apoe KO mice did not.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [61]
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 [58]
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- Authors
- Katsouri, L., & Georgopoulos, S.
- Affiliations
- Biomedical Research Foundation of the Academy of Athens (GR)
- Corresponding author
- Georgopoulos, Spiros
- ORCID
- Katsouri, Loukia
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-07-06
- Volume
- 6
- Issue
- 7
- Pages
- e21880
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3130747
- OpenAlex
- W2134137024
- Cited by
- 72
- References
- 40
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 7 · 2013: 3 · 2012: 8
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Pfizer
- 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
- LDL receptor, Alzheimer's disease, apolipoprotein E, astrocyte activation, microglial activation, glial response, 5xFAD mice, cholesterol metabolism, neuroinflammation
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Astrocytes, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Neuroglia, Protein Processing, Post-Translational, Receptors, LDL, Thiazoles, Amyloid beta-Peptides, Microglia, Mice, Benzothiazoles, Plaque, Amyloid
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.
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