The aggregation of normally soluble amyloid-? (A?) into toxic forms, such as amyloid plaques and oligomers, first begins approximately 10-15 years prior to the onset of cognitive decline associated with Alzheimer's disease (AD). In humans, there is a unique susceptibility of specific brain regions to A? deposition. These regions markedly overlap with the brain's default mode network (DMN). The DMN is a series of brain regions that display high functional connectivity (fc) and neuronal activity while an individual is not engaged in a goal directed task. These regions also demonstrate increased glycolysis, which for the purposes of this PPG refers to glucose uptake in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. It is unclear whether increased glucose/insulin levels can alter glycolysis within the DMN and whether this influences A? levels, synaptic function, or exacerbates AD pathology. This is of interest given the increased risk of AD in patients with diabetes. To understand the relationship between brain glucose/insulin utilization, A? deposition, behavior, fc, and sleep, we have been studying APP/PS1 transgenic (Tg) mice that develop A? plaques in a region-specific pattern similar to that in humans. We have also developed techniques to assess fc in mice using optical imaging (fcOIS). Our published and preliminary data suggest that endogenous synaptic activity and the sleep/wake cycle regulate levels of ISF A? and lactate acutely and A? accumulation chronically. Our preliminary data show that fc in young APP/PS1 Tg mice is normal;however, at 12 months of age, APP/PS1 mice have significant A? deposition and decreased fc as well as disrupted sleep. In this project, we will investigate the mechanisms linking glycolysis, hyperglycemia/ hyperinsulinemia, and sleep deprivation to changes in the default mode network, fc, behavior, and A? deposition. Hypothesis: Hyperglycemia, chronic hyperinsulinemia, and sleep deprivation all increase glycolysis and synaptic A? release, which chronically leads to increased A? deposition in the brain as well as synaptic dysfunction, accelerating the pathogenesis of AD. These ideas will be tested by combining microdialysis, fcOIS, behavior and neuropathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS080675-02
Application #
8707572
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mitra, Anish; Kraft, Andrew; Wright, Patrick et al. (2018) Spontaneous Infra-slow Brain Activity Has Unique Spatiotemporal Dynamics and Laminar Structure. Neuron 98:297-305.e6
Snyder, Abraham Z; Bauer, Adam Q (2018) Mapping Structure-Function Relationships in the Brain. Biol Psychiatry Cogn Neurosci Neuroimaging :
Blazey, Tyler; Snyder, Abraham Z; Su, Yi et al. (2018) Quantitative positron emission tomography reveals regional differences in aerobic glycolysis within the human brain. J Cereb Blood Flow Metab :271678X18767005
Goyal, Manu S; Raichle, Marcus E (2018) Glucose Requirements of the Developing Human Brain. J Pediatr Gastroenterol Nutr 66 Suppl 3:S46-S49
Kraft, Andrew W; Mitra, Anish; Bauer, Adam Q et al. (2017) Visual experience sculpts whole-cortex spontaneous infraslow activity patterns through an Arc-dependent mechanism. Proc Natl Acad Sci U S A 114:E9952-E9961
Su, Yi; Vlassenko, Andrei G; Couture, Lars E et al. (2017) Quantitative hemodynamic PET imaging using image-derived arterial input function and a PET/MR hybrid scanner. J Cereb Blood Flow Metab 37:1435-1446
Andrew, Robert J; Fernandez, Celia G; Stanley, Molly et al. (2017) Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease. Proc Natl Acad Sci U S A 114:E9665-E9674
Reisman, Matthew D; Markow, Zachary E; Bauer, Adam Q et al. (2017) Structured illumination diffuse optical tomography for noninvasive functional neuroimaging in mice. Neurophotonics 4:021102
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
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

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