The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

Dias, Bianca Da Costa; Jovanović, Katarina; Gonsalves, Danielle; Moodley, Kiashanee; Reusch, Uwe; Knackmuss, Stefan; Weinberg, Marc S.; Little, Melvyn; Weiß, Stefan

doi:10.1038/srep05556

Cited by 34 publications

(21 citation statements)

References 53 publications

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“…Life span studies were carried out at 25 or 30°C (adjusted by experimental condition), 70% humidity, on a 12 h light-dark cycle. Flies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were placed in a food vial. Food vials were changed every 3 to 4 d, and the dead flies were counted at that time.…”

Section: Survival Assaymentioning

confidence: 99%

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Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Cheng

Chen

et al. 2018

FASEB j.

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The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated β-amyloid (Aβ) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aβ peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric β-amyloid42 (Aβ42), while autophagy and UPS clear oligomeric Aβ42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Aβ42 clearance, it reduced the life span of Aβ42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Aβ42-induced learning and memory deficits, but there was no effect on Aβ42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Aβ42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

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Section: Survival Assaymentioning

confidence: 99%

“…Increased autophagy accelerates intracellular Ab clearance and reverses cognitive impairments in amyloid precursor protein transgenic mice (19)(20)(21). The ELS endocytoses and degrades plasma membrane proteins, including Ab and amyloid precursor protein (22)(23)(24). Third, all three systems are damaged by Ab.…”

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confidence: 99%

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Cheng

Chen

et al. 2018

FASEB j.

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“…In order to do this, Aβ needs to interact with lipid membranes and cellular receptors [17]. One such receptor is the 37 kDa/ 67 kDa Laminin Receptor Precursor/ High Affinity Laminin Receptor (LRP/LR) [18], also known as LamR1, RPSA and p40 [19]. LRP/LR is a multifunctional receptor mainly found in the lipid raft regions of plasma membranes, as well as in the nucleus [20] and cytoplasm [21].…”

Section: Introductionmentioning

confidence: 99%

“…In AD, LRP/LR, PrP c and Aβ have been shown to function together in order for the disease to progress. LRP/LR acts as a receptor for Aβ42 internalization, co-localizes with amyloid precursor protein (APP), γ-secretase and β-secretase, and interacts directly with the presenilin 1 (PS1) subunit of γ-secretase during the amyloidogenic processing of APP [18,[38][39][40]. Moreover, blockage or downregulation of LRP/LR with the anti-LRP/LR specific antibody, IgG1-iS18, or short hairpin RNAs (shRNAs), respectively, has successfully impeded Aβ shedding and rescued cells from Aβ-induced cytotoxicity [38,39].…”

Section: Introductionmentioning

confidence: 99%

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

Cuttler

Bignoux

Otgaar

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently it has been demonstrated that the 37kDa/67kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Here we show that LRP/LR co-localizes with tau in the perinuclear cell compartment and FRET confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrP c levels, a tauopathy-related protein. Additionally, LRP::FLAG overexpression resulted in increased hTERT levels. These data indicate for the first time a role of LRP/LR in tauopathy of Alzheimer's Disease and recommend LRP::FLAG as a potential alternative therapeutic tool for Alzheimer's Disease treatment through rescuing cells from A induced cytotoxicity and, as shown in this report, decreased phosphorylated tau levels.

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“…Its physiological functions include cellular growth, adhesion, invasion, movement and viability (10). LRP/LR has been found to be a major contributor to the pathogenesis of neoplastic cancers (10), angiogenesis enhancement (12), prion disorders (13)(14)(15) and neurodegenerative diseases such as Alzheimer's disease (16)(17)(18)(19)(20). In addition, upregulation of the receptor has been seen to be implicated in telomerase activity (21).…”

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confidence: 99%

Anti-LRP/LR-Specific Antibody IgG1-iS18 Significantly Impedes Adhesion and Invasion in Early- and Late-Stage Colorectal Carcinoma Cells

Vania

Chetty

Ferreira

et al. 2016

Mol Med

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Cancer is a highly complex disease that has become one of the leading causes of death globally. Metastasis, a major cause of cancer deaths, requires two crucial events, adhesion and invasion. The 37kDa/67kDa laminin receptor (laminin receptor precursor/high-affinity laminin receptor [LRP/LR]) enhances these two steps, consequently aiding in cancer progression. In this study, the role of LRP/LR in adhesion and invasion of early-stage (SW-480 and HT-29) and late-stage (DLD-1) colorectal cancer cells was investigated. Western blotting revealed that early-and late-stage colorectal cancer cells contained significantly higher total LRP/LR levels compared with poorly invasive MCF-7 breast cancer control cells. Flow cytometry revealed that both stages of colorectal cancer displayed significantly higher cell surface LRP/LR levels. Furthermore, upon treatment of colorectal cancer cells with the anti-LRP/LR-specific antibody IgG1-iS18, adhesion to laminin-1 was significantly reduced in both stages. Each stage's invasive potential was determined using the Matrigel™ invasion assay, showing that invasion was significantly impeded in both colorectal cancer stages when the cells were incubated with IgG1-iS18. In addition, Pearson's correlation coefficients propose that both total and cell surface LRP/LR levels are directly proportional to the adhesive and invasive potential of both stages of colorectal cancer. Hence, these findings indicate potential for use of the IgG1-iS18 antibody as a promising therapeutic tool for colorectal cancer patients at both stages.

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The 37kDa/67kDa Laminin Receptor acts as a receptor for Aβ42 internalization

Cited by 34 publications

References 53 publications

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

Anti-LRP/LR-Specific Antibody IgG1-iS18 Significantly Impedes Adhesion and Invasion in Early- and Late-Stage Colorectal Carcinoma Cells

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