Low-density lipoprotein receptor-related protein 8 (LRP8)

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2, is a cell surface receptor belonging to the low-density lipoprotein receptor family that functions as a critical node in both neuronal development and cancer pathology. In the central nervous system, LRP8 serves as the primary receptor for Reelin signaling, mediating neuronal migration and layering during embryonic brain development and contributing to synaptic plasticity and long-term potentiation in the adult brain through interactions with NMDA receptors. In neurodegenerative disease contexts, particularly Alzheimer's disease, LRP8 functions as both an apolipoprotein E receptor and a γ-secretase substrate, implicating it in amyloid-beta formation and clearance pathways. Conversely, LRP8 is frequently overexpressed across multiple cancer types including breast, gastric, prostate, lung, and melanoma, where it promotes cell proliferation, migration, and invasion through activation of PI3K/AKT signaling. Additionally, LRP8 has emerged as a cellular entry receptor for tick-borne encephalitis virus, linking it to infectious disease pathogenesis. The receptor's involvement in both neuroprotection and oncogenic signaling, combined with its complex tissue distribution and functional pleiotropy, positions LRP8 as a challenging but potentially high-value therapeutic target for neurodegenerative and malignant diseases, though selective modulation remains difficult due to compensatory receptor mechanisms and essential developmental functions.

Other names

Apolipoprotein E receptor 2 (ApoER2)LDL receptor-related protein 8

While no approved drugs targeting LRP8 were identified, the receptor's mechanisms that could be therapeutically modulated include: Reelin signaling modulation to enhance or inhibit Reelin-mediated neuronal migration and synaptic plasticity; ApoE signaling modulation for cholesterol transport and amyloid-beta clearance in Alzheimer's disease; PI3K/AKT pathway inhibition to reduce cancer cell proliferation and migration in malignancies with LRP8 overexpression; and viral entry inhibition by blocking TBEV entry through LRP8-mediated endocytosis.