Document text
Principal Investigator: Steven W Barger
Organization: UNIV OF ARKANSAS FOR MED SCIS
Fiscal Year: 2024
Award: $49,447
Funding agency: National Institute on Aging
SUMMARY
Aging is the most powerful risk factor for Alzheimer’s disease (AD), and it contributes to the odds of type-2
diabetes mellitus (T2D) as well. Aging is also associated with a decline in the brain’s use of glucose, its most
important fuel. Astrocytes play a key role in shuttling glucose from the bloodstream to where it is needed by
the neuronal units of activity deeper in the brain tissue. We find evidence of a defect in a key glucose transport
molecule of astrocytes in AD and in a mouse line genetically modified to reproduce some aspects of AD. This
mouse line, overproducing the β-amyloid peptide (Aβ), exhibits dysregulation of circulating glucose, as well as
a decline in brain glucose use. These effects are correlated with poor performance in a test of spatial memory.
Further mimicking human AD, the mice show these problems in the absence of obesity, hyperglycemia,
disruption of appetite, changes in physical activity, pancreatic abnormality, or insulin resistance. Together,
these findings inspire the hypothesis that Aβ, the levels of which begin to rise in the aging brain even without
frank AD, perturbs the ability of astrocytes to bring peripheral glucose to neurons, where it is needed for the
increased neurological activity associated with memory and other functions. This idea will be tested through
studies of the status and function of glucose transport proteins in aging mouse and human brains, along with
comparisons between normal aging, AD, and T2D. Through genetic modification of mice, we will modulate the
levels of the most important astrocytic glucose transporter to determine if it is i) sufficient to bring about
interrupted glucose delivery and memory deficits, and ii) necessary for the presentation of these problems in
an AD model. These studies thus explore a novel hypothesis about a specific element of energy utilization in
the aging brain and its connection to age-related cognitive impairment. As such, the project may provide
innovative strategies for therapeutic intervention.
Terms: <AD dementia><AD model><Adult-Onset Diabetes Mellitus><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's patient><Alzheimers Dementia><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Appetite><Assay><Astrocytes><Astrocytus><Astroglia><Attenuated><Aβ><Benign senescent forgetfulness><Bioassay><Biological Assay><Blood Circulation><Blood Vessels><Bloodstream><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell membrane><Cells><Cerebral cortex><Cerebrum><Chickens><Chronic><Circulation><Cognition><Cognitive><Compensation><Cornu Ammonis><Cytoplasmic Membrane><D-Glucose><Defect><Dependence><Desire for food><Deterioration><Dextrose><Diabetes Mellitus><Disease><Disorder><Elderly><Elements><Encephalon><Endothelium><Energy Expenditure><Energy Metabolism><Erythrocyte/Hepatoma Glucose Transporter><Exhibits><GLUT><GLUT-3 protein><GLUT1><GLUT3><GLUT3 protein><Gallus domesticus><Gallus gallus><Gallus gallus domesticus><Gene Modified><Genetic><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose Transporter 1><Glucose tolerance test><Hippocampus><Human><Humulin R><Hyperglycemia><IPGTT><Impairment><Insulin><Insulin Resistance><Interruption><Isoforms><Ketosis-Resistant Diabetes Mellitus><Link><Maturity-Onset Diabetes Mellitus><Memory><Memory Deficit><Memory Loss><Memory impairment><Mice><Mice Mammals><Modern Man><Modification><Murine><Mus><NIDDM><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Physiology><Neural Cell><Neurocyte><Neurologic><Neurologic function><Neurological><Neurological function><Neuron Degeneration><Neurons><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Obesity><Over weight><Overweight><Pancreas><Pancreatic><Performance><Peripheral><Phenotype><Physical activity><Plasma Membrane><Play><Primary Senile Degenerative Dementia><Process><Protein Isoforms><Proteins><Psyche structure><Regular Insulin><Research Specimen><Resolution><Role><SLC2A1><SLC2A1 gene><Slow-Onset Diabetes Mellitus><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Specimen><Stable Diabetes Mellitus><Supporting Cell><Survey Instrument><Surveys><T2 DM><T2D><T2DM><Testing><Therapeutic><Therapeutic Intervention><Time><Tissues><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Work><a beta peptide><abeta><abeta accumulation><abeta aggregation><adiposity><adult onset diabetes><advanced age><age associated><age associated decline><age associated disease><age associated disorder><age associated effects><age associated impairment><age associated memory decline><age correlated><age dependent><age dependent decline><age dependent disease><age dependent disorder><age dependent impairment><age effect><age linked><age related><age related cognitive deficit><age related cognitive impairment><age related decline><age related effects><age related human disease><age related memory dysfunction><age specific><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><age-related disease><age-related disorder><age-related impairment><aged brain><aging brain><aging effect><alzheimer model><alzheimer risk><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid pathology><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><astrocytic glia><attenuate><attenuates><aβ accumulation><aβ aggregation><behavior test><behavioral test><beta amyloid fibril><blood glucose regulation><brain parenchyma><brain protein Glucose transporter type 3><brain tissue><cell type><cerebral><conditional knock-out><conditional knockout><corpulence><decline with age><diabetes><egg><gene modification><genetically modified><geriatric><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><glucose tolerance><glucose transport><hippocampal><hyper-phosphorylated tau><hyperglycemic><hyperphosphorylated tau><impact of age><impaired glucose tolerance><influence of age><innovate><innovation><innovative><insulin resistant><insulin tolerance><intervention therapy><intraperitoneal glucose tolerance test><ketosis resistant diabetes><maturity onset diabetes><memory decline><memory dysfunction><mental><metabolic rate><natural aging><nervous system function><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><neurophysiological><neurophysiology><normal aging><normative aging><novel><overexpress><overexpression><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><plasmalemma><primary degenerative dementia><resolutions><senile dementia of the Alzheimer type><senior citizen><social role><soluble amyloid precursor protein><solute carrier family 2, facilitated glucose transporter, member 3 protein><spatial memory><trafficking><trait><type 2 DM><type II DM><type two diabetes><uptake><vascular>