Alzheimer's Disease Research
Guojun Bu, Ph.D.
Jacksonville, FL, United States
Title: LRP1 and Insulin Receptor Signaling in AD
Non-Technical Title: Lipoprotein receptor and insulin signaling in Alzheimer's disease and type II diabetes
Duration: April 1, 2010 - March 31, 2013
Award Type: Standard
Award Amount: $400,000
Insulin resistance is a risk factor for Alzheimer's disease (AD) and apoE receptor LRP1 plays critical roles in AD pathogenesis. We intend to dissect how LRP1 and insulin receptors cooperate in regulating the metabolism and toxicity of amyloid beta peptide, which is central to AD. Our work should provide critical knowledge regarding why insulin resistance and type II diabetes are risk factors for AD.
Type II diabetes and insulin resistance are strong risk factors for developing Alzheimer's disease (AD). However, the underlying mechanism is not clear. Our laboratory studies a lipid receptor called LRP1 that plays critical roles in clearing toxic amyloid peptides that build up in AD brains. We have recently found that LRP1 regulates insulin signaling, thereby providing a potential link between AD and diabetes. We intend to study the molecular mechanisms that govern the reciprocal regulation of LRP1 and insulin signaling. Once our study is complete, we predict that we will not only solve the molecular puzzle of AD and diabetes but will also identify novel targets for AD diagnosis and therapy. Our work should also pave the way for future studies aimed at further defining the risk of AD in diabetes patients and address how we can treat patients with diabetes to reduce their risk of developing AD. We will use both cellular and animal models to study how modulation of LRP1 or insulin signaling affects AD pathogenesis. In Aim 1, we will study the molecular mechanism by which lipid receptor LRP1 regulates insulin signaling. In Aim 2, we will examine how LRP1 and insulin signaling affect the metabolism and toxicity of Alzheimer's amyloid beta peptide. Our research will uniquely address how type II diabetes links to AD and help to identify novel targets for AD prevention and therapy. Our experience, expertise and state-of-the-art technology used in this research should ensure the success of our project. These innovative concepts and methodologies place us in a unique position to carry out this exciting project.
Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, Han X, Weeber EJ, Bu G. (2010) Impaired brain lipid metabolism in lipoprotein receptor-deficient mice leads to progressive, age-dependent synapse loss and neurodegeneration. J. Neurosci. 30, 17068-17078.
Kanekiyo T, Zhang J, Liu Q, Liu C-C, Zhang L, Bu G. (2011) Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-? uptake. J. Neurosci. 31, 1644-1651.
Liu Q, Zhang J, Zerbinatti C, Zhan Y, Kolber BJ, Herz J, Muglia LJ, Bu G. (2011) Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. PLoS Biol. 9:e1000575.
Shinohara M, Petersen RC, Dickson DW, Bu G. (2013) Brain regional correlation of amyloid-â with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-â accumulation. Acta. Neuropathol. 125, 535-547.
Liu C-C, Kanekiyo T, Xu H, Bu G. (2013) Apolipoprotein E and Alzheimer’s disease: risk, mechanisms, and therapy. Nat Rev Neurol 9, 106-118.
There is increasing evidence for a connection between Type II diabetes and Alzheimer’s disease (AD). While diabetes is a strong risk factor for AD, problems with insulin signaling and reduced glucose metabolism (sugar breakdown) are also signatures of AD brains. Dr. Bu’s laboratory studies a large protein called LRP1 that plays critical roles in moving brain lipids (fats), and in clearing toxic amyloid proteins that build up in AD brains and injure nerve cells. These researchers have recently found that LRP1 is involved with insulin signaling, a function essential for the health of nerve cells to build and maintain memory. Therefore, the focus of this project is to determine how LRP1 manages insulin signaling and associated functions in AD. In the past year, Dr. Bu’s laboratory established a new technology called microdialysis that allows them to directly measure glucose in the brains of mice. Using this technology, they found that the use of brain glucose is vastly reduced in mice genetically engineered to be missing LRP1 in the brain. They also examined LRP1-regulated insulin signaling in human autopsy brains and found that insulin signaling is indeed impaired in human AD with or without diabetes. Finally, they found that insulin and glucose also determine the levels of LRP1, suggesting that brain glucose and lipid metabolism are highly connected. Together, Dr. Bu’s results provide the links between brain glucose and lipid metabolism, and between AD and diabetes. Their work could be the basis for future design of AD treatments that target the functions of LRP1.