Anti-LRP/LR specific antibodies and shRNAs impede amyloid beta shedding in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia. The amyloid beta (Aβ) peptide is the predominant candidate aetiological agent and is generated through the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by beta (β) and gamma (γ) secretases. Since the cellular prion protein (PrPc) has been shown to regulate Aβ shedding, we investigated whether the cellular receptor for PrPc, namely the 37 kDa/67 kDa Laminin Receptor (LRP/LR) played a role in Aβ shedding. Here we show that LRP/LR co-localises with the AD relevant proteins APP, β- and γ-secretase, respectively. Antibody blockage and shRNA knock-down of LRP/LR reduces Aβ shedding, due to impediment of β-secretase activity, rather than alteration of APP, β- and γ-secretase levels. These findings indicate that LRP/LR contributes to Aβ shedding and recommend anti-LRP/LR specific antibodies and shRNAs as novel therapeutic tools for AD treatment.

Looking into laminin receptor: critical discussion regarding the non‐integrin 37/67‐kDalaminin receptor/RPSAprotein

“…LAMR has been found to contain irregular oxidative modifications in a small‐scale proteomics investigation of the brains of Alzheimer's model mice (Shin et al, ). Modulation of LAMR has also recently been reported to affect Aβ cytotoxicity (Da Costa Dias et al, ) and its release from cells (Jovanovic et al, , ).…”

High Resolution Imaging Study of Interactions between the 37 kDa/67 kDa Laminin Receptor and APP, Beta-Secretase and Gamma-Secretase in Alzheimer's Disease

“…Initial reports suggested not only co-localisation between LRP/LR and β-secretase on the cell surface, but also that these two proteins interacted, as shown by co-immunoprecipitation [22]. The findings presented in Figures 3 and 4 help to further understand the nature of the possible interactions between β-secretase and LRP/LR, where the maximum intensity projection (Figure 3A) constructed from Z-stack images (Figure S2 in File S1) shows strong co-localisation between the 2 proteins within the cellular cytoplasm – this most likely occurring in the endosomes.…”

Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s disease

“…Jovanovic et al [99] found that treating cells with anti-LRP/LR-specific antibody IgG1-iS18 or anti-LRP shRNA resulted in a significant reduction in Ab levels in comparison to the controls (Figure 4). Since it is the overproduction and aggregation of Ab that leads to the development of AD pathology, these results were of great interest, since they revealed a role for LRP/LR in the processes leading to Ab generation, and hence a possible target for future therapeutic strategies.…”