CDB15:0000073 APOE — LRP1

Experimentally validated in Human, Mouse; Orthology-inferred in Human, Rat, Frog, Zebrafish, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep, Mouse

Title

Journal:; Year Published:

Abstract

Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.

Nature, 2012; PubMed, Mus Musculus Apoe — Mus Musculus Lrp1

ABSTRACT: Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.

The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein.

Nature, 1989; PubMed, Homo sapiens APOE — Homo sapiens LRP1

ABSTRACT: The low-density-lipoprotein (LDL) receptor is a cell-surface protein that plays an important part in the metabolism of cholesterol by mediating the uptake of LDL from plasma into cells. Although LDL particles bind to the LDL receptor through their apolipoprotein B (apo B) and apolipoprotein E (apo E) moieties, other apo E-containing particles, like chylomicron remnants, are not dependent on the LDL receptor for uptake into cells. Chylomicrons formed in the intestinal mucosa during the absorption of the products of digestion, are processed by the peripheral circulation by lipoprotein lipase, which catalyses the breakdown of triglycerides in chylomicrons to free fatty acids and glycerol. The resulting chylomicron remnants, which are cholesterol-rich lipoproteins, are subsequently taken up in the liver. A second distinct protein that binds to apo E-containing lipoproteins, but not to LDL, has been proposed to be the receptor mediating the clearance of chylomicron remnants from the plasma. This protein has a relative molecular mass (Mr) of 56,000 (56K). More recent studies have failed, however, to establish whether this protein is a cell-surface receptor. Here we describe crosslinking experiments in which apo E liposomes were found to bind specifically to the cell surface of hepG2 cells and to human liver membranes. The size and immunological cross-reactivity of the protein to which the liposomes bound was indistinguishable from that of the recently cloned and sequenced LDL-receptor-related protein, LRP. We therefore conclude that the LRP might function as an apo E receptor.

Systematic Identification of Cell-Cell Communication Networks in the Developing Brain.

iScience, 2019; PubMed, Mus Musculus Apoe — Mus Musculus Lrp1

ABSTRACT: Since the generation of cell-type specific knockout models, the importance of inter-cellular communication between neural, vascular, and microglial cells during neural development has been increasingly appreciated. However, the extent of communication between these major cell populations remains to be systematically mapped. Here, we describe EMBRACE (embryonic brain cell extraction using FACS), a method to simultaneously isolate neural, mural, endothelial, and microglial cells to more than 94% purity in ∼4 h. Utilizing EMBRACE we isolate, transcriptionally analyze, and build a cell-cell communication map of the developing mouse brain. We identify 1,710 unique ligand-receptor interactions between neural, endothelial, mural, and microglial cells in silico and experimentally confirm the APOE-LDLR, APOE-LRP1, VTN-KDR, and LAMA4-ITGB1 interactions in the E14.5 brain. We provide our data via the searchable "Brain interactome explorer", available at https://mpi-ie.shinyapps.io/braininteractomeexplorer/. Together, this study provides a comprehensive map that reveals the richness of communication within the developing brain.

Basic Information on APOE

Ligand Name: apolipoprotein E

Other Symbols: AD2

Ligand Location: secreted based on hpa, perplexity, uniprot

HGNC Gene Symbol Report: APOE

GeneCards: APOE

HGNC Gene Group: Apolipoproteins

Functional Annotations for APOE

Gene Ontologies: PAN-GO, AmiGO 2

Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)

Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)

Interactions with other Receptors for APOE

APOE — LDLR ・ APOE — LRP2 ・ APOE — LRP5 ・ APOE — LRP8 ・ APOE — SCARB1 ・ APOE — SORL1 ・ APOE — VLDLR ・ APOE — ABCA1 ・ APOE — LILRB3 ・ APOE — LILRB4 ・ APOE — LRP4 ・ APOE — LSR ・ APOE — TREM2

Basic Information on LRP1

Receptor Name: LDL receptor related protein 1

Other Symbols: APR, A2MR, LRP, CD91, LRP1A, APOER, IGFBP3R1, IGFBP-3R

Receptor Location: cell membrane based on hpa, perplexity, uniprot

HGNC Gene Symbol Report: LRP1

GeneCards: LRP1

HGNC Gene Group: MicroRNA host genes, CD molecules, Low density lipoprotein receptors

Functional Annotations for LRP1

Gene Ontologies: PAN-GO, AmiGO 2

Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)

Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)

Interactions with other Ligands for LRP1

A2M — LRP1 ・ APP — LRP1 ・ C1QB — LRP1 ・ C3 — LRP1 ・ C4BPA — LRP1 ・ CALR — LRP1 ・ CCN2 — LRP1 ・ F8 — LRP1 ・ F9 — LRP1 ・ FCN2 — LRP1 ・ HSP90B1 — LRP1 ・ LIPC — LRP1 ・ LPL — LRP1 ・ LRPAP1 — LRP1 ・ LTF — LRP1 ・ MDK — LRP1 ・ MMP13 — LRP1 ・ MMP9 — LRP1 ・ PDGFB — LRP1 ・ PLAT — LRP1 ・ PLAU — LRP1 ・ PSAP — LRP1 ・ SERPINA1 — LRP1 ・ SERPINC1 — LRP1 ・ SERPINE1 — LRP1 ・ SERPINE2 — LRP1 ・ SERPING1 — LRP1 ・ TFPI — LRP1 ・ THBS1 — LRP1 ・ ADAMTS1 — LRP1 ・ APOC3 — LRP1 ・ C1QA — LRP1 ・ CCN1 — LRP1 ・ CEMIP — LRP1 ・ HGFAC — LRP1 ・ HMGB1 — LRP1 ・ HMGB2 — LRP1 ・ HPX — LRP1 ・ HSP90AA1 — LRP1 ・ HSPA1A — LRP1 ・ HSPA4 — LRP1 ・ IGFBP7 — LRP1 ・ LIF — LRP1 ・ MBL2 — LRP1 ・ MMP1 — LRP1 ・ PF4 — LRP1 ・ PLAUR — LRP1 ・ SERPIND1 — LRP1 ・ SFTPA1 — LRP1 ・ SFTPD — LRP1 ・ SLIT2 — LRP1 ・ SPARC — LRP1 ・ TIMP1 — LRP1 ・ TIMP3 — LRP1 ・ TNFAIP6 — LRP1 ・ VWF — LRP1