LRP::FLAG Rescues Cells from Amyloid-β-Mediated Cytotoxicity Through Increased TERT Levels and Telomerase Activity

Bignoux, Monique J; Cuttler, Katelyn; Otgaar, Tyrone C; Ferreira, Eloise; Letsolo, Boitelo T.; Weiß, Stefan

doi:10.3233/jad-190075

Cited by 9 publications

(25 citation statements)

References 65 publications

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“…Wild-type tau is essential for the functioning of microtubules and cell signalling, therefore a decrease in total tau may be detrimental to the cells. However, we have seen that LRP::FLAG overexpression rescues cells from cytotoxicity after treatment with Aβ42 [58]. Therefore, we suggest that the effect of the decreased tau is minimal, otherwise the cells would enter apoptosis as a result of microtubule disintegration and loss of structural integrity.…”

Section: Lrp::flag Overexpression Decreases Total and Phosphorylated mentioning

confidence: 76%

“…In addition, an increase in telomerase activity and hTERT expression was observed with a concomitant reduction in Aβ shedding and intracellular Aβ levels in cells overexpressing LRP::FLAG [58]. Furthermore, this increase in hTERT rescued cells from Aβ-mediated cytotoxicity [58]. Therefore, LRP/LR has a role in the upregulation of telomerase activity and hTERT expression.…”

Section: Introductionmentioning

confidence: 92%

“…Furthermore, Ferreira et al, [42] observed an increase in mTERT in mice treated with the anti-LRP/LR specific antibody, IgG1-iS18 with a concomitant decrease in Aβ peptides and amyloid plaques. In addition, an increase in telomerase activity and hTERT expression was observed with a concomitant reduction in Aβ shedding and intracellular Aβ levels in cells overexpressing LRP::FLAG [58]. Furthermore, this increase in hTERT rescued cells from Aβ-mediated cytotoxicity [58].…”

Section: Introductionmentioning

confidence: 93%

“…Since both LRP/LR and telomerase are known to play a role in the Aβ facet of AD, it was hypothesized that they could also play a role in tauopathy. It is known that overexpression of LRP::FLAG increases hTERT levels in HEK-293 cells [36] and SH-SY5Y cells [58]. It has also been shown that this increase results in an increase in telomerase activity [36,58].…”

Section: Lrp::flag Overexpression Increases Htert and Phospho-tert Lementioning

confidence: 98%

“…It is known that overexpression of LRP::FLAG increases hTERT levels in HEK-293 cells [36] and SH-SY5Y cells [58]. It has also been shown that this increase results in an increase in telomerase activity [36,58]. Thus, western blotting was performed to examine the effect of LRP::FLAG overexpression on hTERT levels, together with the active form of hTERT, phospho-TERT (pS824) ( Figure 4A; C; Figure S6-S7), as this is indicative of an increase in telomerase activity.…”

Section: Lrp::flag Overexpression Increases Htert and Phospho-tert Lementioning

confidence: 99%

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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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Section: Lrp::flag Overexpression Decreases Total and Phosphorylated mentioning

confidence: 76%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 93%

Section: Lrp::flag Overexpression Increases Htert and Phospho-tert Lementioning

confidence: 98%

Section: Lrp::flag Overexpression Increases Htert and Phospho-tert Lementioning

confidence: 99%

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

Cuttler

Bignoux

Otgaar

et al. 2020

Preprint

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Downregulation of LRP/LR with siRNA inhibits several cancer hallmarks in lung cancer cells

et al. 2023

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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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PLGA nanocapsules as a delivery system for a recombinant LRP‐based therapeutic

Bernert,

Bignoux,

Madhav

et al. 2024

FEBS Open Bio

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Telomerase activity is directly affected by the laminin receptor precursor (LRP) protein, a highly conserved nonintegrin transmembrane receptor, which has been shown to have therapeutic effects in ageing, and age‐related diseases. Recently, it has been found that overexpression of LRP‐FLAG, by plasmid transfection, leads to a significant increase in telomerase activity in cell culture models. This may indicate that upregulation of LRP can be used to treat various age‐related diseases. However, transfection is not a viable treatment strategy for patients. Therefore, we present a nanoencapsulated protein‐based drug synthesised using poly(lactic‐co‐glycolic acid) (PLGA) nanocapsules for delivery of the 37 kDa LRP protein therapeutic. PLGA nanocapsules were synthesised using the double emulsification‐solvent evaporation technique. Different purification methods, including filtration and centrifugation, were tested to ensure that the nanocapsules were within the optimal size range, and the BCA assay was used to determine encapsulation efficiency. The completed drug was tested in a HEK‐293 cell culture model, to investigate the effect on cell viability, LRP protein levels and telomerase activity. A significant increase in total LRP protein levels with a concomitant increase in cell viability and telomerase activity was observed. Due to the observed increase in telomerase activity, this approach could represent a safer alternative to plasmid transfection for the treatment of age‐related diseases.

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LRP::FLAG Rescues Cells from Amyloid-β-Mediated Cytotoxicity Through Increased TERT Levels and Telomerase Activity

Cited by 9 publications

References 65 publications

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

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

Downregulation of LRP/LR with siRNA inhibits several cancer hallmarks in lung cancer cells

PLGA nanocapsules as a delivery system for a recombinant LRP‐based therapeutic

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