Novel oxidative pathway targets microglia in Alzheimer's disease

Document text

Principal Investigator: Tatiana V Byzova
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $783,003
Funding agency: National Institute on Aging

Abstract
Alzheimer's disease is the most common dementia characterized by progressive cognitive
decline. By estimates, Alzheimer's disease affects more than one-third of the population over 85,
posing a substantial socioeconomic burden. There is an apparent lack of understanding of the
molecular mechanisms of Alzheimer's disease and reported problems with animal models. These
obstacles prevent the development of new therapeutic strategies, especially their translation to
human patients. This proposal is based on molecular and cellular evidence and an analysis of
human Alzheimer's disease cases. It bridges several aspects of Alzheimer's disease pathology:
discovery of unique oxidative stress pathway, new aspects of microglial biology and dysfunction,
and basic mechanisms of cell adhesion/phagocytosis in the context of disease. We will answer
how exactly oxidation causes microglial dysfunction in Alzheimer's disease and how to
prevent/inhibit their detrimental consequences. Based on our pioneering preliminary studies, we
propose that oxidative stress targets important proteins in microglia responsible for phagocytosis,
leading to deficient phagocytosis and microglia overactivation in Alzheimer's disease. Therefore,
we will focus on the mechanisms of this damage and its prevention in Alzheimer's disease and
other neurodegenerative pathologies. We will develop a new intervention approach (compounds
neutralizing oxidative stress) and uncover new specific targets for the treatment of Alzheimer's
disease.

Terms: <AD dementia><AD pathology><Adhesions><Affect><Age related macular degeneration><Age-Related Maculopathy><Aldehydes><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Amentia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animal Model><Animal Models and Related Studies><Aβ><Biology><Brain><Brain Nervous System><Cell Adhesion><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cellular Adhesion><Chemicals><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Degenerative Neurologic Disorders><Dementia><Development><Disease><Disease Progression><Disorder><Disturbance in cognition><Dysfunction><Economic Burden><Encephalon><Event><Exposure to><Functional disorder><Genetic Alteration><Genetic Change><Genetic defect><Gliosis><Hortega cell><Human><Human Pathology><Impaired cognition><In Vitro><Integrin-mediated Cell Adhesion><Integrin-mediated Cell Adhesion Pathway><Intervention><Intervention Strategies><Lead><Leukocyte Adhesion Deficiency><Ligands><Link><Lipid Peroxidation><Lipids><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methods><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Modification><Molecular><Monitor><Murine><Mus><Mutate><Mutation><Myeloid Cells><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Outcome><Oxidative Stress><Oxidative Stress Induced Gene Expression Via Nrf2><Oxidative Stress Pathway><Pathologic><Pathology><Pathway interactions><Patients><Pb element><Phagocytosis><Physiopathology><Polyunsaturated Fatty Acids><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Prevention><Primary Senile Degenerative Dementia><Process><Protein Modification><Proteins><Proteomics><Receptor Protein><Reporting><Research Specimen><Role><SOD-1><SOD-1 protein><SOD1><SOD1 gene><SOD1 gene product><Site><Specimen><Surface Proteins><System><Technology><a beta peptide><abeta><age associated disease><age associated disorder><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age dependent macular degeneration><age induced macular degeneration><age related human disease><age related macular disease><age related macular dystrophy><age-related disease><age-related disorder><age-related impairment><amyloid beta><amyloid-b protein><beta amyloid fibril><brain tissue><cell sorting><cognitive dysfunction><cognitive loss><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><fatty acid oxidation><genome mutation><gitter cell><heavy metal Pb><heavy metal lead><human disease><in vivo><interventional strategy><membrane structure><mesoglia><microglial cell><microgliocyte><migration><model of animal><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oxidation><oxidative damage><oxidative injury><pathophysiology><pathway><perivascular glial cell><preservation><prevent><preventing><primary degenerative dementia><protein function><protein structure><protein structures><proteins structure><receptor><senile dementia of the Alzheimer type><senile macular disease><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><soluble amyloid precursor protein><superoxide dismutase 1><translation to humans><vesicle transport><vesicular transport>