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LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer's disease mice.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease caused by accumulation of amyloid beta (A?) plaque and neurofibrillary tangle formation. We have shown in vitro, that knock-down and blockade of the 37 kDa/67 kDa Laminin Receptor (LRP/LR) resulted in reduced A? induced cytotoxicity and A? accumulation. In order to test the effect of blocking LRP/LR on A? formation and AD associated symptoms, AD transgenic mice received the anti-LRP/LR specific antibody, IgG1-iS18 through intranasal administration. We show that this treatment resulted in an improvement in memory, and decreased A? plaque formation. Moreover, a significant decrease in A?₄₂ protein expression with a concomitant increase in amyloid precursor protein (APP) and telomerase reverse transcriptase (mTERT) levels was observed. These data recommend IgG1-iS18 as a potentially powerful therapeutic antibody for AD treatment.

SUBMITTER: Ferreira E

PROVIDER: S-EPMC6007457 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer's disease mice.

Ferreira Eloise E Bignoux Monique J MJ Otgaar Tyrone C TC Tagliatti Nicolas N Jovanovic Katarina K Letsolo Boitelo T BT Weiss Stefan F T SFT

Oncotarget 20180605 43

Alzheimer's disease (AD) is a neurodegenerative disease caused by accumulation of amyloid beta (Aβ) plaque and neurofibrillary tangle formation. We have shown <i>in vitro</i>, that knock-down and blockade of the 37 kDa/67 kDa Laminin Receptor (LRP/LR) resulted in reduced Aβ induced cytotoxicity and Aβ accumulation. In order to test the effect of blocking LRP/LR on Aβ formation and AD associated symptoms, AD transgenic mice received the anti-LRP/LR specific antibody, IgG1-iS18 through intranasal ...[more]

PMID: 29930750

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Anti-LRP/LR specific antibody IgG1-iS18 impedes adhesion and invasion of liver cancer cells.

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| S-EPMC4010454 | biostudies-literature

Anti-LRP/LR specific antibody IgG1-iS18 significantly impedes adhesion and invasion in early and late stage colorectal carcinoma cells.

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| S-EPMC5082296 | biostudies-literature

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| S-EPMC3776966 | biostudies-literature

Knock-down of LRP/LR influences signalling pathways in late-stage colorectal carcinoma cells.

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| S-EPMC8035741 | biostudies-literature

Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation.

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| S-EPMC9729883 | biostudies-literature

Knock-down of LRP/LR promotes apoptosis in early and late stage colorectal carcinoma cells via caspase activation.

Project description:BackgroundCancer remains one of the leading causes of death around the world, where incidence and mortality rates are at a constant increase. Tumourigenic cells are characteristically seen to over-express the 37 kDa/67 kDa laminin receptor (LRP/LR) compared to their normal cell counterparts. This receptor has numerous roles in tumourigenesis including metastasis, angiogenic enhancement, telomerase activation, cell viability and apoptotic evasion. This study aimed to expose the role of LRP/LR on the cellular viability of early (SW-480) and late (DLD-1) stage colorectal cancer cells.MethodssiRNA were used to down-regulate the expression of LRP/LR in SW-480 and DLD-1 cells which was assessed using western blotting. Subsequently, cell survival was evaluated using the MTT cell survival assay and confocal microscopy. Thereafter, Annexin V-FITC/PI staining and caspase activity assays were used to investigate the mechanism underlying the cell death observed upon LRP/LR knockdown. The data was analysed using Student's t-test with a confidence interval of 95%, with p-values of less than 0.05 seen as significant.ResultsHere we reveal that siRNA-mediated knock-down of LRP led to notable decreases in cell viability through increased levels of apoptosis, apparent by compromised membrane integrity and significantly high caspase-3 activity. Down-regulated LRP resulted in a significant increase in caspase-8 and -9 activity in both cell lines.ConclusionsThese findings show that the receptor is critically implicated in apoptosis and that LRP/LR down-regulation induces apoptosis in early and late stage colorectal cancer cells through both apoptotic pathways. Thus, this study suggests that siRNA-mediated knock-down of LRP could be a possible therapeutic strategy for the treatment of early and late stage colorectal carcinoma.

| S-EPMC5975593 | biostudies-literature

The first report of RPSA polymorphisms, also called 37/67 kDa LRP/LR gene, in sporadic Creutzfeldt-Jakob disease (CJD).

Project description:BackgroundAlthough polymorphisms of PRNP, the gene encoding prion protein, are known as a determinant affecting prion disease susceptibility, other genes also influence prion incubation time. This finding offers the opportunity to identify other genetic or environmental factor (s) modulating susceptibility to prion disease. Ribosomal protein SA (RPSA), also called 37 kDa laminin receptor precursor (LRP)/67 kDa laminin receptor (LR), acts as a receptor for laminin, viruses and prion proteins. The binding/internalization of prion protein is dependent for LRP/LR.MethodsTo identify other susceptibility genes involved in prion disease, we performed genetic analysis of RPSA. For this case-control study, we included 180 sporadic Creutzfeldt-Jakob disease (CJD) patients and 189 healthy Koreans. We investigated genotype and allele frequencies of polymorphism on RPSA by direct sequencing or restriction fragment length polymorphism (RFLP) analysis.ResultsWe observed four single nucleotide polymorphisms (SNPs), including -8T>C (rs1803893) in the 5'-untranslated region (UTR) of exon 2, 134-32C>T (rs3772138) in the intron, 519G>A (rs2269350) in the intron and 793+58C>T (rs2723) in the intron on the RPSA. The 519G>A (at codon 173) is located in the direct PrP binding site. The genotypes and allele frequencies of the RPSA polymorphisms showed no significant differences between the controls and sporadic CJD patients.ConclusionThese results suggest that these RPSA polymorphisms have no direct influence on the susceptibility to sporadic CJD. This was the first genetic association study of the polymorphisms of RPSA gene with sporadic CJD.

| S-EPMC3171711 | biostudies-literature

LRP-1 variation is not associated with risk of Alzheimer's disease.

Project description:Alzheimer's disease (AD) is characterised by the extensive deposition of amyloid beta (A?) within the parenchyma and vasculature of the brain. It is hypothesised that a dysfunction in A? degradation and/or its removal from the brain may result in accumulation as plaques. Low density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor shown to be involved in cholesterol metabolism but also the removal of A? from the brain. Its ability to transport A? from the brain to the periphery has made it an attractive candidate for involvement in Alzheimer's disease (AD). We have assessed the frequencies of 9 tag- SNPs and the commonly studied synonymous SNP within exon 3 (rs1799986) in a multi-centre AD/control cohort and performed haplotype analysis. We found no evidence from a combined total of 412 controls and 1057 AD patients to support the involvement of LRP-1 variation, including the most commonly studied variant in rs1799986 in conferring genetic susceptibility to increased risk of AD.

| S-EPMC3076756 | biostudies-literature

Nanoscale spatial dependence of avidity in an IgG1 antibody.

Project description:Antibodies are secreted proteins that are crucial to recognition of pathogens by the immune system and are also efficient pharmaceuticals. The affinity and specificity of target recognition can increase remarkably through avidity effects, when the antibody can bind a multivalent antigen through more than one epitope simultaneously. A key goal of antibody engineering is thus to optimize avidity, but little is known about the nanoscale spatial dependence of avidity in antibodies. Here, we develop a set of anti-parallel coiled-coils spanning from 7 to 20 nm and validate their structure using biophysical techniques. We use the coiled-coils to control the spacing between two epitopes, and measure how antigen spacing affects the stability of the bivalent antibody:antigen complex. We find a maximal avidity enhancement at a spacing of 13 nm. In contrast to recent studies, we find the avidity to be relatively insensitive to epitope spacing near the avidity maximum as long as it is within the spatial tolerance of the antibody. We thus only see a ~ twofold variation of avidity in the range from 7 to 20 nm. The coiled-coil systems developed here may prove a useful protein nanocaliper for profiling the spatial tolerance and avidity profile of bispecific antibodies.

| S-EPMC8209022 | biostudies-literature

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