Abstract
The prevalence of Alzheimer's disease (AD) is currently estimated to be around 6 million cases and is predicted to rapidly increase in the coming decades. The currently approved treatments fail to alter the underlying pathophysiology, provide only modest and temporary symptomatic relief and are associated with several side effects. Recent evidence suggests that vascular factors, in particular, lysophosphatidic acid (LPA), the most bioactive component of oxidized low‐density lipoprotein (oxLDL), play a crucial role in the pathophysiology of AD. Increased levels of LPA lead to activation of several intracellular signaling cascades thereby leading to neuroinflammation and neurodegeneration. Statins are cholesterol lowering agents of proven benefit in vascular disease and are also associated with reduction in circulating oxLDL levels. Additionally, several clinical studies suggest the risk of AD was substantially reduced with statins. Hence, the goal of the proposed research is to evaluate the role of the LPA signaling in AD pathogenesis and the effect of statin (atorvastatin) in attenuating LPA induced cognitive dysfunction. In vitro studies utilizing ShSy5y neuronal cell line showed atorvastatin attenuated LPA induced Amyloid beta and tau hyperphosphorylation. The effect of LPA on p38 MAPK Kinase and it's downstream signaling markers of apoptosis (BAX, BCL2) and inflammation (NF‐Kβ, IL‐6, TNFα) was analyzed through biochemical assays. We will utilize a high fat diet mouse model, to investigate the neuroprotective effects of atorvastatin. Novel object location test, Y‐maze and contextual fear conditioning will be performed to evaluate cognitive and behavioral deficits. To assess the effects of LPA and atorvastatin on hippocampal synaptic plasticity, we will measure long term potentiation and long‐term depression, which are the cellular correlates of learning and memory. Golgi cox staining to study the effect of LPA and atorvastatin on dendritic spine morphology is being performed. Western blot will also be used to measure levels of AMPA and NMDA receptor subunits. Biochemical assays will be performed to quantify levels of PSD‐95, synaptophysin, and ARC protein, which are proteins essential for synaptic maturity and plasticity. Finally, the neuroprotective effect of atorvastatin on LPA induced cognitive dysfunction will be analyzed by measuring the levels of autotaxin (ATX), an enzyme important for LPA synthesis. 4, 8‐ and 12‐months aged age. We believe our study will demonstrate that that atorvastatin through its pleotropic effects, attenuate LPA induced cognitive dysfunction by improving behavioral and cognitive deficits, synaptic dysfunction, and reducing the pathologies of AD thereby uncovering a molecular mechanism of LPA induced dyshomeostasis in AD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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