| Gene |
[LDLR](/genes/ldlr) |
| UniProt |
P01130 |
| PDB |
1N7D, 5NJ6 |
| Mol. Weight |
93 kDa |
| Localization |
Cell surface (clathrin-coated pits) |
| Family |
LDLR family (LDL receptor) |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Atherosclerosis](/diseases/atherosclerosis) |
The Low-Density Lipoprotein Receptor (LDLR) is a cell surface receptor that mediates uptake of LDL cholesterol into cells. In the brain, LDLR plays important roles in lipid homeostasis and has been implicated in Alzheimer's disease pathogenesis through its involvement in amyloid-beta clearance and cholesterol metabolism.
LDLR is a type I transmembrane protein with multiple functional domains:
- Ligand-binding repeat domain: Seven LDL-binding repeats (class A repeats)
- EGF precursor homology domain: Contains three EGF-like repeats
- O-linked sugar domain: Contains serine/threonine-rich sequences
- Transmembrane domain: Single pass helix
- Cytoplasmic tail: Contains NPxY motif for clathrin-mediated endocytosis
The receptor undergoes rapid recycling between the cell surface and endosomes.
In the nervous system:
- Cholesterol uptake: Mediates uptake of LDL and other apolipoprotein-containing lipoproteins
- Lipid homeostasis: Regulates brain cholesterol levels through ApoE-containing lipoprotein uptake
- Synaptic function: Involved in synaptic plasticity and function
- Neuronal development: Critical for neuronal survival and process formation
- LDLR polymorphisms associated with AD risk in some populations
- LDLR-mediated uptake of Aβ-apoE complexes
- Regulates brain cholesterol levels, which influence APP processing
- Deletion of LDLR in mice leads to increased Aβ accumulation
- Interaction with Aβ and ApoE in the brain's vascular system
- LDLR affects clearance of Aβ from cerebral vasculature
- Mutations linked to familial CAA
LDLR modulators are being explored for AD therapy:
- Statins (HMG-CoA reductase inhibitors) can upregulate LDLR expression
- LDLR-targeting antibodies to enhance Aβ clearance
- Gene therapy approaches to increase LDLR expression in brain
- LDLR and Aβ clearance (Katsanis et al., 2021)
- LDLR in brain cholesterol homeostasis (Ishii et al., 2018)
- LDLR deficiency and Aβ accumulation (Poirier et al., 2020)