Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1
Open accessAbstract
Mutations in the amyloid precursor protein (APP) cause early-onset Alzheimer's disease (AD), but the only genetic risk factor for late-onset AD is the varepsilon4 allele of apolipoprotein E (apoE), a major cholesterol carrier. Using Cre-lox conditional knockout mice, we demonstrate that lipoprotein receptor LRP1 expression regulates apoE and cholesterol levels within the CNS. We also found that deletion of APP and its homolog APLP2, or components of the gamma-secretase complex, significantly enhanced the expression and function of LRP1, which was reversed by forced expression of the APP intracellular domain (AICD). We further show that AICD, together with Fe65 and Tip60, interacts with the LRP1 promoter and suppresses its transcription. Together, our findings support that the gamma-secretase cleavage of APP plays a central role in regulating apoE and cholesterol metabolism in the CNS via LRP1 and establish a biological linkage between APP and apoE, the two major genetic determinants of AD.
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The APP intracellular domain may increase apoE protein levels by suppressing the transcription of LRP1.
“A recent study demonstrated that the APP intracellular domain may increase apoE protein levels by suppressing the transcription of LRP1, another major apoE receptor in the brain (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 Liu et al., 2007
Knockout 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 Liu et al., 2007
Inactivation 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 [37]
Modulating LRP1 has been reported to affect brain apoE levels.
“Modulating LRP1 has also been reported to affect brain apoE levels (Liu et al., 2007; Zerbinatti et al., 2006)”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Liu et al., 2007
Deletion 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 Liu et al 2007
A series of mechanistic studies suggested that APP intracellular domain (AICD) interacts with the LRP1 promoter and suppresses its transcription.
“A series of mechanistic studies suggested that APP intracellular domain (AICD) interacts with the LRP1 promoter and suppresses its transcription.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Liu et al., 2007
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- Authors
- Liu, Q., Zerbinatti, C. V., Zhang, J., Hoe, H.-S., Wang, B., Cole, S. L., Herz, J., Muglia, L., & Bu, G.
- Affiliations
- Washington University in St. Louis (US)
- Georgetown University Medical Center (US)
- Baylor College of Medicine (US)
- Northwestern University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Bu, Guojun
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 56
- Issue
- 1
- Pages
- 66-78
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2045076
- OpenAlex
- W2033379465
- Cited by
- 364
- References
- 10
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 13 · 2022: 17 · 2021: 10 · 2020: 23 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 22 · 2015: 27 · 2014: 24 · 2013: 26 · 2012: 27
- FWCI
- 19.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2116 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG030128, R01AG027924)
- National Heart, Lung, and Blood Institute (R37HL063762)
- 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
- amyloid precursor protein, apolipoprotein E, LRP1, cholesterol metabolism, Alzheimer's disease, gamma-secretase, APP intracellular domain, Fe65, Tip60, APLP2, lipoprotein receptors, transcriptional regulation, brain cholesterol, late-onset Alzheimer's disease
- MeSH terms
- Lysine Acetyltransferase 5, AICDA (Activation-Induced Cytidine Deaminase), Animals, Animals, Newborn, Apolipoproteins E, Brain, Cell Line, Transformed, Cholesterol, Cytidine Deaminase, Enzyme-Linked Immunosorbent Assay, Cricetinae, Humans, Nerve Tissue Proteins, Nuclear Proteins, Receptors, LDL, RNA, Messenger, Transfection, Trans-Activators, Amyloid beta-Protein Precursor, Mice, Knockout, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Chromatin Immunoprecipitation, Mice, Histone Acetyltransferases, Amyloid Precursor Protein Secretases
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