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Principal Investigator: Wang-Xia Wang
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2024
Award: $666,990
Funding agency: National Institute on Aging
Project Title: MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulation
in Alzheimer’s disease
Abstract
MicroRNAs (miRNA) are small non-coding regulatory RNA that have large impacts in health and disease.
While prior studies have implicated miRNA in Alzheimer’s disease and associated dementias (ADRD), they
have not been used yet in a successful therapeutic strategy. We discovered that microRNA-223 (miR-223), a
miRNA residing on the X-chromosome which is enriched in microglia/macrophage cells, regulates a sexually
dimorphic ApoE pathway via targeting CCAAT-enhancer-binding protein beta (CEBPβ). CEBPβ is an important
regulator of neuroinflammatory response and acts as a transcription factor mediating ApoE expression.
Our recent data showed that deficiency of miR-223 resulted in a substantial, female-biased elevation of
CEBPβ, ApoE, and a heightened inflammatory state in macrophages and in aged mouse brain following a
brain injury. Thus, miR-223 appears to regulate a sexually dimorphic microglia/macrophages-dependent
increase in inflammation and ApoE as brain cells become activated in parallel with age, injury, and/or
Alzheimer’s disease-related pathology. We further demonstrated that miR-223 can be targeted using a novel
miRNA-liposome delivery system. Based on these exciting preliminary results, the main goals of this proposal
are to test the miR-223-CEBPβ pathway in regulating inflammation-triggered ApoE dysregulation in the
biological context of age, sex, and Alzheimer’s disease-relevant brain injury event; and, to test the efficacy of a
novel liposome-miRNA delivery method as a potential therapeutic strategy.
To complete these objectives, we will 1) confirm that miR-223 directly targets the CEBPβ-ApoE pathway in
myeloid cells, and test whether liposome-miR-223 delivery affects this pathway; 2) test the miR-223-CEBPβ-
ApoE pathway using a brain injury mouse model and target the pathway using the liposome miRNA delivery
system in a novel miR-223 knockout mouse; 3) evaluate the miR-223-CEBPβ-ApoE pathway in human cells in
parallel with neuropathological changes of Alzheimer’s disease. These studies will include assessments of
brain tissue from the world-class University of Kentucky Alzheimer’s Disease Center biobank.
Completion of the funded studies will extend our understanding of mechanisms regulating
inflammation/ApoE pathways in the context of sex, aging, and brain injury, ultimately advancing treatments for
Alzheimer’s disease. Filling these knowledge gaps could have a lasting impact on public health. Moreover, our
innovative miRNA-based therapeutic strategy targeting miR-223 provides a proof of efficacy for a new drug
target, particularly in females, who are vulnerable for diseases associated with neuroinflammation and ApoE
dysregulation, including Alzheimer’s disease and other brain injury.
Terms: <40-C-EBP Protein><AD dementia><AD pathology><AGP-EBP Transcription Factor><Acquired brain injury><Acute><Affect><Age><Aging><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease pathology><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amentia><Amyloid (Aβ) plaques><Amyloid Plaques><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Basal Transcription Factor><Basal transcription factor genes><Behavioral Assay><Biochemical><Biological><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain><Brain Injuries><Brain Nervous System><C-EBP-Related Protein 2><C-EBP-beta><C-EBP-β><C-EBPbeta><C-EBPβ><CCAAT-Enhancer-Binding Protein-beta><CCAAT-Enhancer-Binding Protein-β><CRP2 Protein><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Data><Dementia><Disease><Disorder><Disproportionate number of females><Disproportionate number of women><Disproportionately affects females><Disproportionately affects women><Disproportionately impacts females><Disproportionately impacts women><Disproportionately in females><Disproportionately in women><Encephalon><Event><Female><Functional RNA><Funding><General Transcription Factor Gene><General Transcription Factors><Genotype><Goals><Health><Histologic><Histologically><Hortega cell><Human><Human X Chromosome><IL-6 DBP><IL-6-Dependent DNA Binding Protein><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Injury><Interleukin-6 Nuclear Factor><Intracellular Communication and Signaling><Intravenous><KO mice><Kentucky><Knock-out Mice><Knockout Mice><Knowledge><LAP Transcription Factor><Late Onset Alzheimer Disease><Link><Liposomal><Liposomes><Macrophage><Mediating><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Microglia><Modeling><Modern Man><Molecular><Murine><Mus><Myeloid Cells><Mφ><NF-IL6><Nerve Degeneration><Nervous System Physiology><Neuritic Plaques><Neurologic function><Neurological function><Neuron Degeneration><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Null Mouse><Pathology><Pathway interactions><Primary Senile Degenerative Dementia><Proteins><Public Health><RNA><RNA Gene Products><Regulation><Ribonucleic Acid><Role><Sampling><Senile Plaques><Signal Transduction><Signal Transduction Systems><Signaling><System><Testing><Therapeutic><Therapeutically Targetable><Transcription Factor Proto-Oncogene><Transcription factor genes><Universities><Untranslated RNA><X Chromosome><aged><aged mice><aged mouse><ages><alzheimer risk><amyloid beta plaque><amyloid-b plaque><aβ plaques><biobank><biologic><biological signal transduction><biorepository><brain cell><brain damage><brain tissue><brain-injured><cell sorting><cored plaque><diffuse plaque><efficacy testing><elderly mice><female bias><female preponderance><gitter cell><improved><in vivo><injuries><innovate><innovation><innovative><late onset alzheimer><lipid based nanoparticle><lipid nanoparticle><liposomal delivery><liposome delivery><male><mesoglia><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA delivery><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA delivery><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><microglial cell><microgliocyte><mouse model><murine model><nervous system function><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal degeneration><neuropathologic><neuropathological><neuropathology><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><noncoding><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><old mice><pathway><perivascular glial cell><primary degenerative dementia><protein biomarkers><protein markers><response><senile dementia of the Alzheimer type><sex><sex dimorphism><sexual dimorphism><sexually dimorphic><social role><systemic inflammation><systemic inflammatory response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><transcription factor><women's preponderance>