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Principal Investigator: Alexandra Munch
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $47,374
Funding agency: National Institute on Aging
PROJECT SUMMARY
Alzheimer’s disease (AD) is a grave neurodegenerative disorder characterized by unrelenting memory loss and
deficits in executive function with no effective treatment. Accumulating evidence from genome wide association
studies (GWAS) posit that the brain’s innate immune system plays a central role in AD etiology. As the central
nervous system’s resident immune cells, microglia have thus emerged as attractive cells to target therapeutically.
Such drug targets may lie within the MS4A locus, a region associated with protection from AD, later age-at-
onset, and increased levels of sTREM2, a biomarker of microglial activity. This region contains multiple genes
within the membrane-spanning 4-domain subfamily A (MS4A) gene cluster, which together encode structurally
related transmembrane proteins largely expressed by immune cells whose exact functions are not yet
understood. Our work nominated a candidate causal variant within this locus, rs636317, which disrupts an anchor
binding site for the chromatin remodeling protein CTCF and is associated with increased expression of MS4A4A
and MS4A6A in myeloid cells. This proposal aims to directly test the hypothesis that by modulating MS4A4A and
MS4A6A expression via differential CTCF binding, variant rs636317 alters microglial cell function in the context
of disease. In AIM 1, I will determine the functional impact of MS4A genes in vitro using CRISPR-edited human
induced pluripotent stem cell (iPSC)-derived microglia (iMGL). Given known interactions between MS4A proteins
and other immune receptors such as TREM2 and CLEC7A, I will perform targeted functional assays related to
immune signaling in iMGLs from two iPSC models: MS4A4A/MS4A6A knockout lines and isogenic lines
homozygous for the protective or risk alleles of the candidate causal variant. In AIM 2, I will employ a novel
xenotransplantation model involving direct injection of human microglia precursor cells into the mouse brain to
evaluate the effect of these genes on cell function in vivo and in the context of disease using 5xFAD chimeric
mice. I hypothesize that knocking out MS4A4A and MS4A6A in human microglia promotes protective microglial
responses, ameliorating plaque containment and subsequent cognitive decline. Elucidating the function of this
gene family and the specific role it plays in AD progression has the potential to greatly impact public health. The
proposed research and rigorous training plan outlined here will equip me with the skills needed for a successful
future career in neurodegeneration leading an independent research team.
Terms: <AD dementia><Active Oxygen><Affect><Age><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease risk><Alzheimer's disease therapeutic><Alzheimer's therapeutic><Alzheimers Dementia><Amyloid (Aβ) plaques><Amyloid Plaques><Amyloid deposition><Animal Model><Animal Models and Related Studies><Assay><Binding><Binding Proteins><Binding Sites><Bioassay><Biological><Biological Assay><Biological Function><Biological Markers><Biological Process><Brain><Brain Nervous System><CCCTC-binding factor><CNS Nervous System><CRISPR><CRISPR/Cas system><CTCF protein><Causality><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Signaling><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Central Nervous System><Chromosome 11><Clustered Regularly Interspaced Short Palindromic Repeats><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Combining Site><Containment><DNA-binding protein CTCF><Data Set><Degenerative Neurologic Disorders><Diathesis><Disease><Disease Progression><Disease susceptibility><Disorder><Disturbance in cognition><Drug Targeting><Encephalon><Enhancers><Etiology><Foundations><Future><GWA study><GWAS><Gene Cluster><Gene Expression><Gene Family><Gene variant><Genes><Genetic><Genetic Diseases><Genomics><Genotype><Heterograft><Heterologous Transplantation><Hortega cell><Human><Human Genetics><Immune><Immune signaling><Immunes><Immunologic Receptors><Immunological Receptors><Impaired cognition><In Vitro><Injections><Innate Immune System><Integral Membrane Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Investigators><Knock-out><Knockout><Ligand Binding Protein><Ligand Binding Protein Gene><Light><Macrophage><Maps><Measures><Mediating><Membrane><Memory Deficit><Memory Loss><Memory impairment><Methods><Mice><Mice Mammals><Microglia><Modern Man><Molecular Interaction><Morphology><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neuritic Plaques><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Nucleotides><Outcome><Oxygen Radicals><Pathologic><Phagocytosis><Phenotype><Photoradiation><Play><Primary Senile Degenerative Dementia><Pro-Oxidants><Production><Progenitor Cells><Protein Binding><Proteins><Public Health><Reactive Oxygen Species><Reactive Site><Research><Research Personnel><Researchers><Risk><Risk-associated variant><Role><Senile Plaques><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Single-Nucleus Sequencing><Statistical Study><Strains Cell Lines><Subcellular Process><TREM2><TREM2 gene><Techniques><Testing><Training><Translating><Transmembrane Protein><Transmembrane Protein Gene><Transplantation><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Validation><Variant><Variation><Work><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><ages><allele variant><allelic variant><alzheimer risk><amyloid beta plaque><amyloid pathology><amyloid-b plaque><aβ plaques><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><bound protein><career><causal allele><causal gene><causal mutation><causal variant><causation><causative mutation><causative variant><cell culture><cell cultures><cell type><chromatin remodeling><cognitive dysfunction><cognitive loss><cored plaque><cultured cell line><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diffuse plaque><disease causation><disease risk><disorder risk><drug development><drug discovery><effective therapy><effective treatment><epigenomics><executive control><executive function><experiment><experimental research><experimental study><experiments><functional genomics><gene function><genetic condition><genetic disorder><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><gitter cell><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><humanized mice><humanized mouse><iPS><iPSC><iPSCs><immune receptor><in vitro Model><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><innovate><innovation><innovative><liability to disease><loss of function><member><membrane structure><memory decline><memory dysfunction><mesoglia><microglial cell><microgliocyte><model of animal><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><p-tau><p-τ><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><precursor cell><primary degenerative dementia><progenitor cell model><progenitor model><protective allele><protective variant><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><selective expression><selectively expressed><senile dementia of the Alzheimer type><single nucleotide variant><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tau phosphorylation><tau posttranslational modification><tau-1><therapeutically effective><transcriptomics><transplant><validations><whole genome association analysis><whole genome association studies><whole genome association study><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model><τ phosphorylation>