Investigating the Impact of Novel Senescent Microglia in Alzheimer's Disease Progression
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Principal Investigator: Matthew J Yousefzadeh Organization: MAYO CLINIC ROCHESTER Fiscal Year: 2024 Award: $295,223 Funding agency: National Institute on Aging Title: Inves�ga�ng the Impact of Novel Senescent Microglia in Alzheimer's Disease Pathology Abstract: Alzheimer's Disease (AD) is a debilita�ng neurodegenera�ve disorder with a cri�cal need for improved therapeu�c strategies. One controversial component of AD progression is the role of microglia, the brain's immune cells. Recent research indicates a subpopula�on of these cells exhibi�ng senescence characteris�cs, raising the ques�on if these senescent microglia might contribute to AD progression through a senescence-associated secretory phenotype (SASP). Our proposal aims to elucidate the role of these cells in AD using a two-fold approach: defining and characterizing these senescent microglia through proteomic, transcriptomic, and spa�al-omics profiling (Aim 1) and inves�ga�ng whether removing these senescent microglia can slow or delay AD progression (Aim 2). We plan to leverage a novel transgenic mouse model to selec�vely ablate newly iden�fied senescent microglia and assess the subsequent impact on AD progression. If successful, these studies could offer novel insight into AD pathology and iden�fy poten�al therapeu�c targets by focusing on the selec�ve elimina�on of senescent microglia. Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><AD dementia><AD model><AD pathology><Ablation><Abscission><Advanced Development><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Amyloid (Aβ) plaques><Amyloid Plaques><Biologic Characteristic><Biological Characteristics><Biology><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><CRE Recombinase><Cell Aging><Cell Body><Cell Function><Cell Membrane Proteins><Cell Physiology><Cell Process><Cell Senescence><Cells><Cellular Aging><Cellular Function><Cellular Physiology><Cellular Process><Cellular Senescence><Cognition><Cognitive><Corynebacterium Diphtheriae Toxin><Data><Degenerative Neurologic Disorders><Deterioration><Development><Diphtheria Toxin><Disease><Disease Marker><Disease Progression><Disease associated microglia><Disorder><Dysfunction><Encephalon><Encephalon Diseases><Enterobacteria phage P1 Cre recombinase><Estrogen Receptors><Excision><Extirpation><Family><Functional disorder><Genes><Health Care Systems><Healthcare Systems><Hortega cell><Immune><Immunes><Impairment><Innate Immunity><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Investigation><Learning><Link><LoxP-flanked allele><Mediating><Methods><Mice><Mice Mammals><Microglia><Murine><Mus><Native Immunity><Natural Immunity><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurites><Neuritic Plaques><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Specific Immunity><Nonspecific Immunity><Outcome Study><Pathologic><Patients><Phenotype><Physiologic><Physiological><Physiopathology><Pilot Projects><Play><Preventive><Primary Senile Degenerative Dementia><Production><Proteins><Proteome><Proteomics><RNA Seq><RNA sequencing><RNAseq><Removal><Replicative Senescence><Research><Risk-associated variant><Role><Senile Plaques><Site><Stimulus><Stress><Subcellular Process><Surgical Removal><Tamoxifen><Testing><Therapeutic><Tissues><Transgenic Mice><Transgenic Organisms><Up-Regulation><Upregulation><Work><aged mice><aged mouse><aging associated disease><aging related disease><alzheimer model><amyloid beta plaque><amyloid-b plaque><aβ plaques><bacteriophage P1 recombinase Cre><cored plaque><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diffuse plaque><digital><disease of aging><disorder of aging><elderly mice><floxed><floxed allele><gitter cell><global gene expression><global transcription profile><glycoprotein NMB><gpNMB><hyper-phosphorylated tau><hyperphosphorylated tau><improved><innovate><innovation><innovative><insight><insoluble aggregate><mesoglia><microglial cell><microgliocyte><mouse model><murine model><nano-string><nanostring><natural aging><neural inflammation><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurotoxic><normal aging><normative aging><novel><old mice><p-tau><p-τ><pathophysiology><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><pilot study><post-translational modification of tau><posttranslational modification of tau><preservation><prevent><preventing><primary degenerative dementia><promoter><promotor><protein aggregate><protein aggregation><resection><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stressor><tau phosphorylation><tau posttranslational modification><tau-1><therapeutic target><therapeutically effective><tool><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transgenic><τ phosphorylation>