Alzheimer's disease (AD) is estimated to affect over 5 million Americans. A significant risk factor for AD is particularly mid-life obesity. In itself, obsity also represents a tremendous health concern for the U.S. with its suggested epidemic levels. Therefore, any strategy to ameliorate either or both conditions is extremely attractive therapeutically. We propose that the relationship between AD and obesity is not correlative but that there may be a common pathophysiology. It is well known that mutations in the gene coding for amyloid precursor protein, APP, are responsible for autosomal dominant forms of AD. However, our preliminary data indicates that APP is critically required for weight gain and the associated brain and adipose changes that occur in a murine model of high fat diet-induced obesity. APP expression is actually required for efficient uptake of fatty acids into cells. Therefore, we hypothesize that APP regulates diverse cellular differentiation involving, in particular, changes in lipid metabolism that regulates adipocytes, neurons, and macrophage/microglia during diet-induced obesity. Dysregulation or alteration of this biology by mutant APP will have ramifications during obesity but, more importantly, during AD. We will first test this hypothesis quantifying the ability of wild type and mutant APP and any associated signaling or processing to regulate adipocyte, macrophage/microglia, and neuron phenotype in vitro. We will then define a role for APP in tissue specific changes during diet-induced obesity in vivo using wild type and mutant APP expressing mice compared to APP-/- mice. By defining the role of normal and mutant forms of APP in regulating cellular phenotype in adipose tissue depots and brain we will explain how APP contributes directly to diet-induced obesity and possibly to progression of AD. This not only offers a common mechanistic pathophysiology of these two diseases but also targets APP and its associated signaling response for therapeutic intervention.

Public Health Relevance

This study will validate a novel mechanism by which amyloid precursor protein regulates the ability of cells to metabolize and utilize fatty acids. This biolog is particularly important for the changes that occur in adipose tissue but also in the brain and immune cells during the condition of diet-induced obesity. Because expression of mutant forms of amyloid precursor protein produces Alzheimer's disease, we speculate that the role of amyloid precursor protein in regulating lipid metabolism is also related to mechanisms of Alzheimer's disease. Defining the function of amyloid precursor protein in diet-induced obesity will not only offer insight into the pathophysiology of obesity but also that of Alzheimer's diseas.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG042819-04
Application #
8878970
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
2012-08-01
Project End
2016-06-30
Budget Start
2015-08-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Dakota
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Golovko, Svetlana A; Golovko, Mikhail Y (2018) Plasma Unesterified Fatty-Acid Profile Is Dramatically and Acutely Changed under Ischemic Stroke in the Mouse Model. Lipids 53:641-645
Kulas, Joshua A; Hettwer, Jordan V; Sohrabi, Mona et al. (2018) In utero exposure to fine particulate matter results in an altered neuroimmune phenotype in adult mice. Environ Pollut 241:279-288
Kulas, Joshua A; Puig, Kendra L; Combs, Colin K (2017) Amyloid precursor protein in pancreatic islets. J Endocrinol 235:49-67
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Manocha, Gunjan D; Ghatak, Atreyi; Puig, Kendra L et al. (2017) NFATc2 Modulates Microglial Activation in the A?PP/PS1 Mouse Model of Alzheimer's Disease. J Alzheimers Dis 58:775-787
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Nagamoto-Combs, Kumi; Manocha, Gunjan D; Puig, Kendra et al. (2016) An improved approach to align and embed multiple brain samples in a gelatin-based matrix for simultaneous histological processing. J Neurosci Methods 261:155-60
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Manocha, Gunjan D; Floden, Angela M; Rausch, Keiko et al. (2016) APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease. J Neurosci 36:8471-86
Brose, Stephen A; Golovko, Svetlana A; Golovko, Mikhail Y (2016) Brain 2-Arachidonoylglycerol Levels Are Dramatically and Rapidly Increased Under Acute Ischemia-Injury Which Is Prevented by Microwave Irradiation. Lipids 51:487-95

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