Low Density Lipoprotein Receptor-Related Proteins (LRPs), Alzheimers and Cognition
M. E. Harris-White and S. A. Frautschy
Affiliation: 16111 Plummer Street (151), Sepulveda, CA 91343, USA.
Keywords: synapse, alzheimers disease, apolipoprotein e, cognition, signaling, transforming growth factor beta, plasticity, clearance
This review will focus primarily on the role of the low density lipoprotein receptor-related protein (LRP-1) in neuronal synapse formation and function in Alzheimers Disease (AD). We review the role that its ligands may have in cognition or AD: apolipoprotein E (ApoE), α2-macroglobulin, Transforming Growth Factor-Beta (TGFβ), Tissue Plasminogen Activator (tPA), insulin growth factor binding protein-3 (IGFBP-3), which all bind LRP-1 and apolipoprotein J (ApoJ), which is a ligand for LRP-2. After reviewing its role as a signaling receptor, we discuss the connection between LRP and the NMDA glutamate receptor via the post synaptic density 95 (PSD-95) neuronal scaffold protein and the implications it may have for memory and cognition. Finally, we discuss the evidence supporting a role for LRP in AD. Although the evidence for LRP as a genetic risk factor is weak, many of its ligands impose genetic risk, and have been implicated in AD pathogenic cascades. We discuss the role of LRP in amyloid precursor protein (APP) processing and production of beta-amyloid (Aβ). We identify LRP ligands that accelerate aggregation of toxic Aβ species. LRP mediates crucial pathways in AD pathogenesis such as Aβ clearance, Aβ uptake, intraneuronal Aβ accumulation and A associated neuron death. Interestingly, the TGFβ-V receptor is LRP-1. Data show that one critical ligand TGFβ2, associated with neurodegeneration in amyloid diseases, induces LRP expression in PC12 cells. Data from rodent infusion models demonstrate the impact of TGFβ2in modifying Aβ induced Long Term Potentiation (LTP) responses, presynaptic proteins, lipid peroxidation, gliosis and staining for neuronal nuclei. The evidence supports a complex and significant role of LRP in cognition and AD.
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