Luz De Dios ¹, Camille Collazo ², Yaritza Inostroza-Nieves¹

1 Department of Biochemistry, San Juan Bautista School of Medicine, Caguas, Puerto Rico

2 Department of Biology, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico


Alzheimer’s Disease (AD) is the most common cause of dementia. AD is a neurodegenerative disorder characterized by the deterioration in cognition, function, and behavior. Histologic pathognomonic findings show an increase in extracellular amyloid b (A b ) plaques and intracellular hyperphosphorylated tau (p-tau) neurofibrillary tangles in neurons. Recent studies have shown association between the Renin-Angiotensin-System (RAS) and the development of the cognitive impairment seen in AD patients. The involvement of RAS has been mediated through the activation of Angiotensin II type I receptors (AT1R) by Angiotensin II (AngII), which is overexpressed in aging brains. However, the exact mechanism of how the signaling pathway ofAng II contributes to AD is unknown. Thus, we hypothesize that Ang II increases p-tau by activating its kinases, cyclin-dependent kinase 5 (CDK5) and mitogen activated protein kinase (MAPK) and increases the production of Reactive Oxygen Species (ROS), leading to neurotoxicity and neuronal death. The objective of this study was to evaluate the effect of Ang II on p-tau and ROS production in human cortical neuron cell line, HCN2. In these cells, treatment with AngII upregulated the gene expression of CDK5 (2.9 folds, p<0.0001, n=4) and MAPK (1.9 folds, p<0.001, n=4).

The changes in tau kinases were blocked by the AT1R antagonist, Losartan. Also, AngII induced the MAPK activation, increasing its phosphorylation by 400% (p<0.0001, n=4), an increase that was also blocked by Losartan. An increase in tau phosphorylation by AngII was observed using fluorescent microscopy. We then quantified ROS production by using MUSE Oxidative Stress assay. In these cells, ROS production were significantly increased by AngII (p<0.01, n=4) and treatment with Losartan blunted their production (p<0.05, n=4). The data obtained demonstrated that AngII may contribute to the pathogenesis of AD. This way, the AngII antagonist, Losartan could be used as treatment for AD.

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