Investigating the effect of LRP/LR and telomerase on tauopathy in alzheimer's disease cell culture models

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2019

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Cuttler, Katelyn

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder resulting in dementia in the elderly. Currently, approximately 50 million people worldwide are suffering from AD. This disease is a result of two neuropathological features, extracellular amyloid plaques caused by aggregation of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles caused by accumulation of hyperphosphorylated tau protein. Tau is a microtubuleassociated protein that normally functions to stabilize microtubules. Hyperphosphorylation of tau causes its dissociation from microtubules, ultimately leading to cell death. Furthermore, levels of the human reverse transcriptase ((hTERT) subunit of telomerase, has been shown to be significantly decreased in tau-affected neuronal cells. Normally, hTERT would function to protect cells from oxidative stress. Therefore, the absence of hTERT enhances neurodegeneration. It has recently been demonstrated that the 37 kDa/ 67 kDa laminin receptor (LRP/LR) interacts with telomerase leading to increases in both telomerase activity and hTERT levels. Furthermore, LRP/LR is known to play a role in Alzheimer’s disease as a receptor for Aβ42 internalization and is involved in the amyloidogenic processing of amyloid precursor protein (APP). This study investigates whether overexpression of LRP::FLAG, with a concomitant increase in hTERT levels, will change total tau and phosphorylated tau levels in vitro. To address this question, we overexpressed LRP::FLAG in vitro and investigated total tau, phosphorylated tau, hTERT, Aβ42 and PrPc levels. LRP/LR and tau colocalize in the perinuclear cell compartment and Försters Resonance Energy Transfer (FRET) confirmed a direct interaction between LRP/LR and tau. Thereafter, cells were transfected with the pCIneo-moLRP-FLAG plasmid in order to overexpress LRP::FLAG. Western blotting and confocal microscopy confirmed a decrease in total tau and phosphorylated tau levels in cells overexpressing LRP::FLAG. Therefore, LRP::FLAG overexpression could lead to a decrease in neurofibrillary tangle formation. Western blotting also confirmed an increase in hTERT levels, which could rescue AD-affected cells from the cytotoxicity caused by Aβ42 and tau. Furthermore, the levels of Aβ42 and PrPc, two tauopathy-related proteins, were also shown to decrease. Therefore, a reduction in both Aβ42 and PrPc could result in less tau hyperphosphorylation and neurofibrillary tangle formation. This is the first study to show that there is an interaction between LRP/LR and tau and the results suggest that overexpression of LRP::FLAG may be a possible treatment strategy for the tauopathy of AD

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