LRP1
Prolow-density lipoprotein receptor-related protein 1 precursor (LRP-1) (Alpha-2-macroglobulin receptor) (A2MR) (Apolipoprotein E receptor) (APOER) (CD91 antigen) [Contains: Low-density lipoprotein receptor-related protein 1 85 kDa subunit (LRP-85); Low-density lipoprotein receptor-related protein 1 515 kDa subunit (LRP-515); Low-density lipoprotein receptor-related protein 1 intracellular domain (LRPICD)] [A2MR] [APR]
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Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient ([i]ldlr[/i] ) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.
MeSH Terms
- Animals
- Atherosclerosis
- Cellular Senescence
- Diet, Western
- Disease Models, Animal
- Indoleacetic Acids
- Macrophages
- Metabolic Syndrome
- Mice
- Mice, Knockout
- Obesity
- Plaque, Atherosclerotic
- Plasminogen Activator Inhibitor 1
- Receptors, LDL
Keywords
- atherosclerosis
- cellular senescence
- fibrinolysis
- metabolic syndrome
- muscle, smooth
- obesity
- plasminogen activator inhibitor-1
The vascular hypothesis of Alzheimer's disease postulates that disruption of the brain microvasculature is important for the accumulation of amyloid beta and increased neuroinflammation. Liver X Receptor agonist, GW3965, has been demonstrated to successfully modulate neuroinflammation and lipid metabolism in murine models of AD. This is partially due to increased expression of ApoE levels and increased mobility of endothelial progenitor cells. This paper analyzes changes in the neurovascular unit and in astrocytes and microglia markers following oral administration of GW3965 in a very old triple transgenic AD mice (3xTg-AD mice). We found that astrogliosis, but not activation of microglia, decreased in very old (24 months) 3xTg-AD mice treated with GW965. In addition, GW3965 increased LRP1 levels in neuron-like cells and partially restored microvascular morphology by decreasing tortuosity and increasing length as shown by Lectin immunostaining. Interestingly, these changes were associated with decreased Aβ in blood vessels. In conclusion, short-term treatment of 3xTg-AD mice with GW3965 restored microvascular architecture which may be important in the cognitive improvement previously shown.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Astrocytes
- Benzoates
- Benzylamines
- Biomarkers
- Glial Fibrillary Acidic Protein
- Hippocampus
- Liver X Receptors
- Mice
- Mice, Transgenic
- Microglia
- Microvessels
- Neurons
Keywords
- Alzheimer’s disease
- GW3965
- Liver x receptors
- Neuroinflammation
- Neurovascular endothelium
Apolipoprotein E (apoE) plays a critical role in maintaining synaptic integrity by transporting cholesterol to neurons through the low-density lipoprotein receptor related protein-1 (LRP1). Bexarotene, a retinoid X receptor (RXR) agonist, has been reported to have potential beneficial effects on cognition by increasing brain apoE levels and lipidation. To investigate the effects of bexarotene on aging-related synapse loss and the contribution of neuronal LRP1 to the pathway, forebrain neuron-specific LRP1 knockout (nLrp1(-/-)) and littermate control mice were administered with bexarotene-formulated diet (100mg/kg/day) or control diet at the age of 20-24 months for 8 weeks. Upon bexarotene treatment, levels of brain apoE and ATP-binding cassette sub-family A member 1 (ABCA1) were significantly increased in both mice. While levels of PSD95, glutamate receptor 1 (GluR1), and N-methyl-d-aspartate receptor NR1 subunit (NR1), which are key postsynaptic proteins that regulate synaptic plasticity, were decreased with aging, they were restored by bexarotene treatment in the brains of control but not nLrp1(-/-) mice. These results indicate that the beneficial effects of bexarotene on synaptic integrity depend on the presence of neuronal LRP1. However, we also found that bexarotene treatment led to the activation of glial cells, weight loss and hepatomegaly, which are likely due to hepatic failure. Taken together, our results demonstrate that apoE-targeted treatment through the RXR pathway has a potential beneficial effect on synapses during aging; however, the therapeutic application of bexarotene requires extreme caution due to its toxic side effects.
MeSH Terms
- ATP Binding Cassette Transporter 1
- Aging
- Animals
- Apolipoproteins E
- Bexarotene
- Brain
- Calcium-Binding Proteins
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Disks Large Homolog 4 Protein
- Gene Expression Regulation
- Guanylate Kinases
- Liver Diseases
- Low Density Lipoprotein Receptor-Related Protein-1
- Male
- Membrane Proteins
- Mice
- Mice, Transgenic
- Microfilament Proteins
- Nerve Tissue Proteins
- Neuroglia
- Receptors, AMPA
- Receptors, LDL
- Receptors, N-Methyl-D-Aspartate
- Retinoid X Receptors
- Synapses
- Tetrahydronaphthalenes
- Tumor Suppressor Proteins
Keywords
- Aging
- Bexarotene
- LRP1
- Nuclear receptor
- RXR agonist
- Retinoid
- Synapse
- apoE
In Alzheimer's disease (AD), accumulation of brain amyloid-β (Aβ) depends on imbalance between production and clearance of Aβ. Several pathways for Aβ clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Aβ clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Aβ clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance (125)I-Aβ40 clearance. Also, the increase in brain and hepatic clearance of (125)I-Aβ40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Aβ endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Aβ major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Aβ clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology.
MeSH Terms
- Aging
- Amyloid beta-Peptides
- Animals
- Blood-Brain Barrier
- Brain
- Cholinesterase Inhibitors
- Donepezil
- Enzyme-Linked Immunosorbent Assay
- Indans
- Liver
- Male
- Piperidines
- Rats
- Rats, Sprague-Dawley
- Rivastigmine
Keywords
- Alzheimer’s disease
- BBB
- Donepezil
- amyloid-β clearance
- liver
- rivastigmine
The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age-specific, isoform-dependent effects of ApoE on neuronal signaling.
MeSH Terms
- Aging
- Animals
- Apolipoprotein E4
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Female
- Gene Expression Regulation, Developmental
- Humans
- Low Density Lipoprotein Receptor-Related Protein-1
- Memory
- Mice
- Mice, Transgenic
- Neurons
- Phosphorylation
- Protein Isoforms
- Receptors, LDL
- Receptors, N-Methyl-D-Aspartate
- Signal Transduction
- Tumor Suppressor Proteins
Low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells. Mice in which the lrp1 gene is deleted in smooth muscle cells (smLRP1(-/-)) on a low-density lipoprotein receptor-deficient background display excessive platelet derived growth factor-signaling, smooth muscle cell proliferation, aneurysm formation, and increased susceptibility to atherosclerosis. The objectives of the current study were to examine the potential of LRP1 to modulate vascular physiology under nonatherogenic conditions. We found smLRP1(-/-) mice to have extensive in vivo aortic dilatation accompanied by disorganized and degraded elastic lamina along with medial thickening of the arterial vessels resulting from excess matrix deposition. Surprisingly, this was not attributable to excessive platelet derived growth factor-signaling. Rather, quantitative differential proteomic analysis revealed that smLRP1(-/-) vessels contain a 4-fold increase in protein levels of high-temperature requirement factor A1 (HtrA1), which is a secreted serine protease that is known to degrade matrix components and to impair elastogenesis, resulting in fragmentation of elastic fibers. Importantly, our study discovered that HtrA1 is a novel LRP1 ligand. Proteomics analysis also identified excessive accumulation of connective tissue growth factor, an LRP1 ligand and a key mediator of fibrosis. Our findings suggest a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HtrA1 and connective tissue growth factor protein levels. This study highlights 2 new molecules, connective tissue growth factor and HtrA1, which contribute to detrimental changes in the vasculature and, therefore, represent new target molecules for potential therapeutic intervention to maintain vessel wall homeostasis.
MeSH Terms
- Age Factors
- Aging
- Animals
- Aorta
- Aortitis
- Blood Pressure
- Cells, Cultured
- Connective Tissue Growth Factor
- Dilatation, Pathologic
- Elastic Tissue
- Endocytosis
- Enzyme Activation
- Extracellular Matrix
- Extracellular Signal-Regulated MAP Kinases
- Fibrosis
- High-Temperature Requirement A Serine Peptidase 1
- Ligands
- Low Density Lipoprotein Receptor-Related Protein-1
- Male
- Mice
- Mice, Knockout
- Myocytes, Smooth Muscle
- Proteomics
- Receptors, LDL
- Serine Endopeptidases
- Tumor Suppressor Proteins
Keywords
- Ctgf protein, mouse
- HtrA1 protein, mouse
- Lrp1 protein, mouse
- collagen
- lamina elastica
Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ~70% of amyloid β-peptide (Aβ) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Aβ peripheral binding and higher levels of free Aβ in plasma. Experimental studies have shown that free circulating Aβ re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Aβ from entering the brain. Treatment of Alzheimer APPsw( /0) mice with WT-LRPIV has been shown to reduce brain Aβ pathology. In addition to Aβ, LRPIV binds multiple ligands. To enhance LRPIV binding for Aβ relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Aβ40 and Aβ42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Aβ40 and Aβ42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw( /0) mice with LRPIV-D3674G (40 μg/kg/day) reduced Aβ40 and Αβ42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aβ clearance therapy.
MeSH Terms
- Alzheimer Disease
- Amino Acid Substitution
- Amyloid beta-Peptides
- Animals
- CHO Cells
- Cerebral Cortex
- Cerebrovascular Circulation
- Cricetinae
- Cricetulus
- Hippocampus
- Humans
- Ligands
- Low Density Lipoprotein Receptor-Related Protein-1
- Mice
- Mice, Mutant Strains
- Mutation, Missense
- Peptide Fragments
- Protein Binding
- Receptors, LDL
- Tumor Suppressor Proteins
Keywords
- Aging
- Alzheimer Disease
- Amyloid
- Amyloid Precursor Protein
- Amyloid-beta
- Clearance Therapy
- LRPIV Mutant
- Lipoprotein Receptor
- Neurodegenerative Diseases
- sLRP1