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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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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 :
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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
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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