Lysophosphatidic Acid Induces Tau Hyperphosphorylation by Dysregulation of Kinase and Phosphatases
Type of DegreePhD Dissertation
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The increased incidence of Alzheimer’s disease (AD) indicates an unmet medical need to develop novel molecular targets for therapeutic potential. Alzheimer’s disease is primarily classified into early-onset (genetic) and late-onset (sporadic), depending on the age of the onset. Metabolic disease (e.g., dyslipidemia, obesity, insulin resistance) is associated with an increased risk of developing AD. Dyslipidemia is characterized by an increase in low-density lipoproteins (LDL), and oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA). Lysophosphatidic acid is a major bioactive lipid that acts through G protein-coupled receptors (GPCRs) and plays an essential role in mediating cellular signaling processes. Dysregulated LPA levels in the brain and increased LPA signaling activity have been associated with various neurological and neurodegenerative diseases, including AD. However, the signaling mechanisms by which LPA causes tau hyperphosphorylation have not been investigated. This work aimed to address this issue as an essential step in evaluating the role of LPA in regulating kinases and phosphatases that are known to cause tau hyperphosphorylation. In the current study, we provide evidence that LPA causes the activation of several kinases, such as ERK1/2, CDK5, and GSK3β, leading to tau hyperphosphorylation at the AT8 epitope. Next, we found that LPA induces a pro-inflammatory response in neuronal and microglial cells by activating the cGAS-STING and NF-κB pathways. Furthermore, LPA causes mitochondrial dysfunction and oxidative stress in neuronal cells. Finally, our preliminary data shows that atorvastatin, a statin used to treat dyslipidemia, prevents tau hyperphosphorylation at the AT8 site by inhibiting multiple kinases and activating phosphatase. The results reported here support the view that selectively targeting LPA signaling by atorvastatin may be helpful in AD and other neurodegenerative diseases; accordingly, the work discusses further steps towards the translation of the present findings.