The impact of obesity-induced hepatic amyloid beta dysregulation on Alzheimer’s disease pathology - PROJECT SUMMARY The long-term goal of this proposal is to determine how obesity modulates the liver-brain axis to induce and/or promote Alzheimer’s disease (AD) pathology. Obesity and high fat/sugar diet are risk factors of AD, but the mechanism is not completely understood. Obesity significantly affects the liver, causing fatty liver (liver steatosis), which can progress to more severe liver diseases such as non-alcoholic steatohepatitis (NASH) and cirrhosis. Our exciting recent data suggests that liver steatosis induced by obesity (ob/ob mice) or chronic alcohol feeding causes the downregulation of hepatic lipoprotein receptor-related protein 1 (LRP1), the major hepatic receptor that removes amyloid-β (Aβ) from the periphery, while simultaneously upregulates hepatic amyloid precursor protein (APP), an important source of Aβ in the periphery and brain. The question of whether obesity- induced steatotic liver, where APP is overexpressed and LRP1 in downregulated, can promote cerebral amyloidosis and AD pathology, is unknown, merits further investigation, and is the focus of the current proposal. This proposal will provide an integrated examination of how obesity-induced liver steatosis and hepatic Aβ dysregulation affects cerebral Aβ levels to promote AD pathology through the following specific aims: Aim 1) Examine the relationship between changes in peripheral and hepatic Aβ with brain Aβ load and AD pathology in AD mice fed a high fat/high sucrose diet (Western diet; WD). Our working hypothesis is that dysregulation in hepatic Aβ processing (increased APP and decreased LRP1) induced by WD increases hepatic, and thereby, peripheral Aβ levels, that increase brain Aβ load to enhance AD pathology. By examining both human and mouse Aβ and APP, and key proteins involved in Aβ homeostasis (BACE1, LRP1, IDE, and neprilysin) in the liver and brain of WD-fed AD (APP/PS1) and WT mice, we will: a) determine if obesity-induced hepatic and peripheral Aβ dysregulation correlates with brain Aβ load and AD pathology (tau phosphorylation, gliosis, neuronal loss, cognition), and b) determine if obesity-induced hepatic Aβ dysregulation impacts healthy (WD-fed WT mice) and pathologic (WD-fed APP/PS1 mice) brains differently. Aim 2) Determine the significance of hepatic APP and LRP1 in regulating peripheral and brain Aβ, and AD pathology in AD mice. Our working hypothesis is that hepatic APP overexpression and LRP1 silencing, as seen with liver steatosis, increase hepatic, peripheral and brain Aβ levels to enhance AD pathology. The effect of specific targeting of hepatic APP (overexpression using adeno- associated virus 8 (AAV8). TBG viral vector) and LRP1 (silencing using a AAV8.TBG.miRNA viral vector) on peripheral and cerebral Aβ, and AD pathology in APP/PS1 mice will highlight the specific contributions of these proteins in AD. The proposal will combine specialists in the areas of liver research with AD research to provide an integrated examination of the liver-brain axis in obesity-induced AD utilizing state-of-the-art techniques including spatial proteomics. The resulting knowledge may identify new therapeutic-targets and mechanisms of obesity-linked AD and will define the significance of obesity-linked hepatic Aβ dysregulation in AD pathology.
