Search results for "LRP1"

LRP1 mediates bidirectional transcytosis of amyloid-β across the blood-brain barrier.

2011

According to the "amyloid hypothesis", the amyloid-β (Aβ) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated transcytosis of Aβ across the BBB we analyzed Aβ transcytosis across primary mouse brain capillary endothelial cells (pMBCECs) derived from wild-type and LRP1 knock-in mice. Here, we show that pMBCECs in vitro express functionally active LRP1. Moreover, we demonstrate that LRP1 mediates transcytosis of [(125)I]-Aβ(1-40) across pMBCECs in both direct…

The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development

2014

Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migra…

Functional Role of Lipoprotein Receptors in Alzheimers Disease

2008

The LDL receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer's disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/apolipoprotein E (ApoE) uptake, with the epsilon4 allele of ApoE as the strongest genetic risk factor for late-onse…

Functional role of the low-density lipoprotein receptor-related protein in Alzheimer's disease.

2006

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, characterized by neuronal loss, neurofibrillary tangle formation and the extracellular deposition of amyloid-β (Aβ) plaques. The amyloid precursor protein (APP) and the enzymes responsible for Aβ generation seem to be the base elements triggering the destructive processes. Initially, the low-density lipoprotein receptor-related protein (LRP) was genetically linked to AD and later it emerged to impact on many fundamental events related to this disease. LRP is not only involved in Aβ clearance but is also the major receptor of several AD-associated ligands, e.g. apolipoprotein E and α<sub>2</sub>-m…

No association of alcohol dependence with a NMDA-receptor 2B gene variant

2003

The Functional Role of the Second NPXY Motif of the LRP1 β-Chain in Tissue-type Plasminogen Activator-mediated Activation of N-Methyl-D-aspartate Rec…

2008

The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of …

LRP1 modulates APP trafficking along early compartments of the secretory pathway

2008

The amyloid beta peptide (A beta) is a central player in Alzheimer's disease (AD) pathology. A beta liberation depends on APP cleavage by beta- and gamma-secretases. The low density lipoprotein receptor related protein 1 (LRP1) was shown to mediate APP processing at multiple steps. Newly synthesized LRP1 can interact with APP, implying an interaction between these two proteins early in the secretory pathway. We wanted to investigate whether LRP1 mediates APP trafficking along the secretory pathway, and, if so, whether it affects APP processing. Indeed, the early trafficking of APP within the secretory pathway is strongly influenced by its interaction with the C-terminal domain of LRP1. The …

Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis

2012

Bacterial pathogens modulate host cell apoptosis to establish a successful infection. Pore-forming toxins (PFTs) secreted by pathogenic bacteria are major virulence factors and have been shown to induce various forms of cell death in infected cells. Here we demonstrate that the highly conserved caspase-2 is required for PFT-mediated apoptosis. Despite being the second mammalian caspase to be identified, the role of caspase-2 during apoptosis remains enigmatic. We show that caspase-2 functions as an initiator caspase during Staphylococcus aureus alpha-toxin- and Aeromonas aerolysin-mediated apoptosis in epithelial cells. Downregulation of caspase-2 leads to a strong inhibition of PFT-mediate…

The stem rust resistance gene Rpg5 encodes a protein with nucleotide-binding-site, leucine-rich, and protein kinase domains

2008

We isolated the barley stem rust resistance genes Rpg5 and rpg4 by map-based cloning. These genes are colocalized on a 70-kb genomic region that was delimited by recombination. The Rpg5 gene consists of an unusual structure encoding three typical plant disease resistance protein domains: nucleotide-binding site, leucine-rich repeat, and serine threonine protein kinase. The predicted RPG5 protein has two putative transmembrane sites possibly involved in membrane binding. The gene is expressed at low but detectable levels. Posttranscriptional gene silencing using VIGS resulted in a compatible reaction with a normally incompatible stem rust pathogen. Allele sequencing also validated the candi…

Analysis of the LRP10 gene in patients with Parkinson's disease and dementia with Lewy bodies from Southern Italy

2020

Recently, the LRP10 gene has been associated with Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). The aim of the present study was to evaluate the presence of mutations of the LRP10 gene in patients with PD or DLB from Southern Italy. Sequencing analysis revealed only 2 missense and 3 synonymous variants in patients and control subjects and a rare variant p.L622F in a PD case. These results suggest that LRP10 mutations are not a frequent cause of PD and DLB in Southern Italy.