The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. Our interest in glycolysis arose from several observations made by us leading up to this proposal. Glycolysis accounts for 12 to15% of glucose metabolized by the adult human brain. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN consists of areas in medial and lateral parietal cortices, dorsal and ventral medial prefrontal cortex and the medial temporal cortices. It is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis o any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Because diabetes has emerged as a significant risk factor for Alzheimer's disease caused us to consider these two diseases together in terms of how glucose metabolism might not only serve to define a specific network of areas in the brain but also increase the vulnerability of these areas to Alzheimer's disease. In the experiments proposed, we ask how brain glycolysis and resting-state functional connectivity are regulated by age, sleep and systemic alterations in glucose homeostasis and insulin sensitivity. We specifically hypothesize that chronic hyperglycemia and insulin resistance as well as sleep deprivation increase glycolysis and A? release in brain areas, such as the DMN, that are heavily reliant on glycolysis, leading to increased A? deposition and accelerating the pathogenesis of AD. Project 1 and 2 will explore how brain glycolysis and functional connectivity in the DMN are regulated by systemic alterations in glucose homeostasis and insulin sensitivity in populations at risk for AD (older individuals and people with T2DM), and experiments in Project 3 will enable ideas tested in Projects 1 and 2 to be taken from the systems neuroscience level to the cellular and molecular level.

Public Health Relevance

This work will provide critically needed mechanistic links between glycolysis (glucose use outside of oxidative phosphorylation), diabetes (a risk factor for Alzheimer's disease - AD) and the brain's default mode network (DMN), a network uniquely dependent on glycolysis and a primary target of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS080675-02
Application #
8707569
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Babcock, Debra J
Project Start
2013-07-15
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Su, Yi; Rubin, Brian B; McConathy, Jonathan et al. (2016) Impact of MR-Based Attenuation Correction on Neurologic PET Studies. J Nucl Med 57:913-7
Harris, Richard A; Tindale, Lauren; Lone, Asad et al. (2016) Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis. J Neurosci 36:1871-8
Stanley, Molly; Macauley, Shannon L; Holtzman, David M (2016) Changes in insulin and insulin signaling in Alzheimer's disease: cause or consequence? J Exp Med 213:1375-85
Mitra, Anish; Snyder, Abraham Z; Hacker, Carl D et al. (2016) Human cortical-hippocampal dialogue in wake and slow-wave sleep. Proc Natl Acad Sci U S A 113:E6868-E6876
Su, Yi; Blazey, Tyler M; Owen, Christopher J et al. (2016) Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group. PLoS One 11:e0152082
Jin, Yan; Su, Yi; Zhou, Xiao-Hua et al. (2016) Heterogeneous multimodal biomarkers analysis for Alzheimer's disease via Bayesian network. EURASIP J Bioinform Syst Biol 2016:12
Su, Yi; Vlassenko, Andrei G; Couture, Lars E et al. (2016) Quantitative hemodynamic PET imaging using image-derived arterial input function and a PET/MR hybrid scanner. J Cereb Blood Flow Metab :
Stanley, Molly; Macauley, Shannon L; Caesar, Emily E et al. (2016) The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice. J Neurosci 36:11704-11715
McAvoy, Mark; Mitra, Anish; Coalson, Rebecca S et al. (2016) Unmasking Language Lateralization in Human Brain Intrinsic Activity. Cereb Cortex 26:1733-46
Raichle, Marcus E (2015) The restless brain: how intrinsic activity organizes brain function. Philos Trans R Soc Lond B Biol Sci 370:

Showing the most recent 10 out of 26 publications