Alzheimer’s disease (AD) is a neurodegenerative disease caused by accumulation of amyloid beta (Aβ) 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 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 administration. We show that this treatment resulted in an improvement in memory, and decreased Aβ plaque formation. Moreover, a significant decrease in Aβ42 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.
Background: Alzheimer's disease (AD) is characterized by amyloid- (A) 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 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in A pathology. Since both LRP/LR and telomerase are known to play a role in the A facet of AD, we hypothesized that they might also play a role in tauopathy.Objective: This study aimed to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins. Methods: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-SY5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting. Results: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and 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. LRP::FLAG overexpression also resulted in increased hTERT levels. Conclusion: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels.
The incidence and mortality rates of cancer are growing rapidly worldwide, with lung cancer being the most commonly occurring cancer in males. Human carcinomas circumvent the inhibitory pathways induced by DNA damage and senescence through the upregulation of telomerase activity. The 37 kDa/67 kDa laminin receptor (LRP/LR) is a cell surface receptor which plays a role in several cancer hallmarks, including metastasis, angiogenesis, cell viability maintenance, apoptotic evasion, and mediating telomerase activity. We have previously shown that the knockdown of LRP/LR with an LRP‐specific siRNA significantly impedes adhesion and invasion, induces apoptosis, and inhibits telomerase activity in various cancer cell lines in vitro. Here, we investigated the effect of downregulating LRP/LR with LRP‐specific siRNA in A549 lung cancer cells. Downregulation of LRP/LR resulted in a significant decrease in cell viability, migration potential, and telomerase activity, as well as a significant increase in apoptosis. Proteomic analysis further suggested the re‐establishment of immune control over the lung cancer cells, a previously unidentified facet of LRP downregulation in cancer. Altogether, we suggest that targeting LRP/LR for downregulation may have therapeutic potential for inhibiting several cancer hallmarks.
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