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Principal Investigator: Peggi M Angel
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $756,289
Funding agency: National Institute on Aging
Abstract:
Alzheimer’s disease (AD) is a devastating diagnosis and there is a critical need to understand the fundamental
molecular pathogenesis of AD to design effective therapies. In addition to the well-known AD pathologies,
perturbed glucose metabolism is also a clinical feature of AD. Glycogen and N-linked glycans are two critically
important but understudied facets of glucose metabolism. Both glycogen and N-linked glycans are complex
carbohydrates that play vital roles in brain physiology such as cognition, memory formation, and life span.
Despite the importance of these pathways in normal brain function, whether complex carbohydrate metabolism
are perturbed during AD disease progression remains a critical knowledge gap in neurobiology. In exciting
preliminary data, we discovered profound glycogen accumulation and protein hyperglycosylation in the
prefrontal cortex of both mouse models of AD and human AD specimens. Further, we found a positive
correlation between increased glycogen and Braak staging in an analysis of a 97-patient cohort. Finally, oral
glucosamine supplement, a precursor to UDP-N-acetylglucosamine biosynthesis, building block of N-linked
glycans further exacerbated hyperglycosylation and led to poorer cognitive performance in the 5xFAD mouse
model of AD. Based on these preliminary data, we hypothesize that aberrant complex carbohydrate
metabolism are pathogenic processes during AD disease progression. The major objective of this study is to
systematically resolve cellular and extracellular origins of perturbed complex carbohydrate metabolism using
state-of-the-art single cell technologies. We will achieve this through synergistic integration of multi-parameter
single-cell mass spectrometry imaging methodologies. First, we will define complex carbohydrates with clinical
course and disease progression in patient samples (Aim 1). Then, we will interrogate cellular and extra-cellular
architecture in normal and AD patient samples (Aim 2). Finally, we will apply multimodal integration to track
cellular and extracellular origins of complex carbohydrate perturbation in AD (Aim 3). This study will provide
critical new information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic
modulation of AD. Collectively, we believe the resultant findings from this proposal will be highly salient for
multiple related fields of Alzheimer’s disease and other neurodegenerative disorders.
Terms: <2-Amino-2-Deoxyglucose><2-amino-2-deoxy-D-glucose><3-D><3-Dimensional><3D><AD associated neurodegeneration><AD dementia><AD model><AD neurodegeneration><AD pathology><Age><Algorithms><Alzheimer Type Dementia><Alzheimer associated neurodegeneration><Alzheimer disease dementia><Alzheimer related neurodegeneration><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease associated neurodegeneration><Alzheimer's disease brain><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's disease related neurodegeneration><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amentia><Ammon Horn><Anabolism><Architecture><Astrocytes><Astrocytus><Astroglia><Biological><Body Tissues><Brain><Brain Nervous System><Brain region><CNS Diseases><CNS Nervous System><CNS disorder><Carbohydrates><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Clinical><Clinical Course of Disease><Co-Translational Protein Modification><Co-Translational Protein Processing><Code><Coding System><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Cornu Ammonis><Cotranslational Protein Modification><Cotranslational Protein Processing><Data><Degenerative Neurologic Disorders><Dementia><Development><Diagnosis><Dimensions><Disease><Disease Progression><Disorder><Disturbance in cognition><ECM><Education><Educational aspects><Encephalon><Endothelium><Engineering / Architecture><Event><Extracellular Matrix><Glia><Glial Cells><Glucosamine><Glycans><Glycogen><Goals><Heterogeneity><Hippocampus><Hortega cell><Human><Image><Impaired cognition><Intermediary Metabolism><Investigators><Knowledge><Kolliker's reticulum><Link><MALD-MS><MALDI><MALDI-MS><Maps><Measures><Memory><Metabolic><Metabolic Glycosylation><Metabolic Processes><Metabolism><Metadata><Methodology><Microglia><Modern Man><Molecular><Multiplexed Ion Beam Imaging><Multivariate Analyses><Multivariate Analysis><Neighborhoods><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurobiology><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic Degenerative Conditions><Neurons><Non-neuronal cell><Nonneuronal cell><Oral><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Patients><Physiology><Play><Polysaccharides><Prefrontal Cortex><Primary Senile Degenerative Dementia><Process><Proteins><Proteomics><Regional Anatomy><Research Personnel><Research Specimen><Researchers><Role><Sampling><Slice><Specimen><Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization><Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization><Staging><Study models><Subcellular Process><Therapeutic><Time><Tissue imaging><Tissues><ages><alzheimer model><analysis pipeline><astrocytic glia><biologic><biosynthesis><carbohydrate metabolism><cell imaging><cellular imaging><cerebrovascular pathology><cognitive dysfunction><cognitive loss><cognitive performance><cohort><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><effective therapy><effective treatment><extracellular><gitter cell><glucose metabolism><glycosylation><hippocampal><human disease><imaging><imaging approach><imaging based approach><imaging mass spectrometry><imaging platform><insight><life span><lifespan><mass spectrometric imaging><matrix assisted laser desorption ionization><mesoglia><meta data><microglial cell><microgliocyte><mouse model><multi-modality><multimodality><murine model><nano meter scale><nano meter sized><nanometer scale><nanometer sized><nanoscale><nerve cell death><nerve cell loss><nerve cement><neurobiological><neurodegenerative illness><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic><neuropathological><neuropathology><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><perivascular glial cell><primary degenerative dementia><protein folding><senile dementia of the Alzheimer type><sex><single cell technology><social role><three dimensional>