Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway

Abstract

The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-␤ peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-␤-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.Originally described as a clearance receptor for lipoproteins in the liver, the low density lipoprotein receptor-related protein 1 (LRP1) 2 plays essential roles in development and mediates important tissue-specific functions throughout adulthood. These include regulation of glutamatergic synaptic transmission in the nervous system, prevention of vascular smooth muscle cell proliferation and atherosclerosis development, catabolism of activated coagulation factor VIII in hepatocytes, and regulation of body energy by adipocytes (1, 2). Mounting evidence suggests an important role for LRP1 in the pathogenesis of Alzheimer disease (AD). LRP1 regulates the production and clearance of amyloid-␤ (A␤) peptide and the metabolism of several AD-associated ligands, including apolipoprotein E (apoE), which has three isoforms in humans with apoE4 being a major risk factor for late onset AD (3). LRP1 is abundantly expressed in the cell body and proximal processes of cortical and hippocampal neurons in the brain (4 -6). It consists of an extracellular 515-kDa subunit (LRP1-515) that binds more than 30 different ligands and a transmembrane 85-kDa chain (LRP1-85) that interacts with several adaptor proteins for efficient endocytic trafficking and signaling (7). LRP1 binds to A␤ either directly or via A␤ chaperones, such as apoE, to mediate A␤ clearance (3,8,9). In AD patients and in the elderly, brain LRP1 levels are significantly decreased and inversely correlate with the age of onset of...

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

“…This could potentially result in the formation of RBD-A␤ complexes (24) that accelerate ␤-amyloid-mediated neuronal degeneration (54). Yet other reports indicate that LRP1 agonists might reduce aberrant amyloid precursor protein processing (55) and that LRP1-dependent cell signaling in neurons and glia appears to consistently result in prosurvival effects (56). Moreover, the LRP1 ligand derived from the hemopexin domain of matrix metalloproteinase 9, PEX, does not bind A␤ and would be unlikely to influence Alzheimer's disease-related pathology.…”

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

“…In the neurons of dendritic synapses, LRP1 interacts with the N-methyl-D-aspartate receptor to modulate neuronal calcium signaling (15). Neuronal expression of LRP1 also activates protein kinase B/Akt signaling in protection against stress-induced apoptosis (16). In addition, LRP1 has been shown to participate in focal adhesion and cell migration via direct association with integrins and/or modulation of calreticulin/thrombospondin signaling events (17,18).…”

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

“…98,99) A deficiency of LRP1 in neurons induces activation of caspase 3, a decrease of Akt phosphorylation and a decrease in the level of the insulin receptor, as well as the progression of apoptosis. 100) Binding of ligands, such as tissue-type plasminogen activator or a2-macroglobulin, to LRP1 in neurons transactivates the Trk receptor by activation of Src family kinase, suggesting that these ligands may have neurotrophic activity. 101) We have also reported that another ligand for LRP1, apo E associated with lipid, induces a strong anti-apoptotic effect and protects against neurodegeneration through an intracellular signaling pathway.…”