2001 — 2003 |
Ikezu, Tsuneya |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Antiretroviral Activities of Nebri @ University of Nebraska Medical Center
Utilizing recombinant mRNA differential display a novel cDNA, termed Nebraska One (NEBR1), was cloned from HIV-1 infected monocyte- derived macrophages. NEBR1 functions as a transcriptional repressor with demonstrated anti-retroviral properties. Expressed copiously in HIV-1 infected mononuclear phagocytes (MP), NEBR1, could represent a unique innate immune. We hypothesize that NEBR1 is a natural cellular suppressor of HIV-1 that plays a role in both modulating macrophage function and viral infection during persistent disease. The relationship between NEBR1 and HIV-1 p24 expression in brain MP makes it of special interest to HIV-1 encephalitis and its associated dementia. To these ends we propose to elucidate: (1) the steps of HIV-1 life cycle in which NEBR1 suppresses HIV-1 replication (including HIV-1 entry, HIV-1 DNA synthesis, its genomic integration, and gene transcription from HIV DNA); (2) the DNA binding motif of NEBR1, and (3) the promoter/enhancer region(s) of NEBR1 that are activated by HIV-1. The intent of this proposal is to determine how NEBR1 is regulated and how it effects HIV-1 replication. The potential of NEBR1 to effect viral-host cell interactions is realistic, novel and contains therapeutic implications.
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0.961 |
2005 — 2009 |
Ikezu, Tsuneya |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Otk18 Regulation in Hiv-1 Associated Dementia @ University of Nebraska Medical Center
DESCRIPTION (provided by applicant): The transcriptional factor, OTK18, has recently been shown by our group to regulate HIV-1 infection in mononuclear phagocytes (MP). Interestingly, OTK18 is specifically expressed in the cytosol of brain MP in severe HIV-1 encephalitis but not in other neurodegenerative disorders and may thus serve as a "surrogate" marker for the development of HIV-associated dementia (HAD). To further develop these observations we will determine why OTK18 can be expressed at relatively high levels in advanced disease and yet fail to control viral growth in brain target cells. Our preliminary data indicates that the E-twenty six-1 binding sequence (EBS) of the HIV-1 long termminal repeat is a critical element for OTK18 suppression. EBS is also located in the proximal region of the OTK18 promoter, suggesting an autoinhibitory mechanism of gene expression. In this application, we hypothesize that EBS binding along with OTK18 endoproteolysis regulate OTK18 activity in HAD. Furthermore, we will address the discrepency between high OTK18 levels in disease. and its anti-retroviral functions. We believe this apparent contradiction to be due to endoproteolytic cleavage of OTK18 in infected macrophages leading to its cytoplasmic localization and viral escape from OTK18 suppression. In that context, viral escape from OTK18 suppression will correlate with HAD. To examine these hypotheses, the following questions will be asked:1) What is the mechanism(s) for HIV-1 induction of OTK18 expression?, 2) What is the mechanism of viral from OTK18 suppression in HAD?, and 3) What is the mechanism of OTK18 endoproteolysis? We posit that molecular characterization of OTK18 will lead to a better understanding of the dual complex roles of MP viral regulation and its role in the neuropathogensis of HIV-1 infection. We will address the following specific aims; 1) To study the role of promoter elements in OTK-18 function. 2) To study the mechanism of viral escape from OTK18 suppression in HAD, and 3) To characterize OTK18 processing and function. The proposed research is innovative, as viral regulation by a zinc finer protein and escape from OTK18 suppression by EBS mutation is a new paradigm. Our findings may also have an important impact in the field of zinc finger molecules, since OTK18 is located on chromosome 19q13, where clusters of retroviral integration sites and zinc fingers are evolutionally co-localized.
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0.961 |
2007 |
Ikezu, Tsuneya |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Genome-Wide Screening of Host Genes Involved in Virus-Induced Neurotoxic Signali @ University of Nebraska Lincoln |
0.961 |
2008 — 2012 |
Ikezu, Tsuneya |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Cells and Tissue Core @ University of Nebraska Medical Center
0-6 weeks old; 21+ years old; AIDS Dementia; AIDS Dementia Complex; AIDS Virus; AIDS neuropathy; AIDS with dementia; AIDS-related dementia; Acquired Immune Deficiency Syndrome related dementia; Address; Adult; Age; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Apoplexy; Astrocytes; Astrocytus; Astroglia; Autopsy; Biological; Birth Defects; Blood leukocyte; Blood monocyte; Body Tissues; Bone Marrow; Brain; Cell Count; Cell Function; Cell Number; Cell Process; Cell model; Cell physiology; Cell/Tissue, Immunohistochemistry; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular model; Cerebral Stroke; Cerebrospinal Fluid; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Collection; Commit; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Malformation; Core Facility; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia Complex, AIDS-Related; Dementia Complex, Acquired Immune Deficiency Syndrome; Dementia Due to HIV Disease; Dementia associated with AIDS; Dementia in human immunodeficiency virus (HIV) disease; Dementia with Lewy Bodies; Dementia, Alzheimer Type; Dementia, Lewy Body; Dementia, Primary Senile Degenerative; Dementia, Senile; Diagnosis; Diffuse Lewy Body Disease; Disease; Disorder; ENPT; Embryo; Embryonic; Encephalon; Encephalons; End Point; EndPointCode; Endpoints; Ensure; Equilibrium; Experimental Designs; Femur; Fetal Age; Fetal Maturity, Chronologic; Fetal Tissues; Freezing; Funding; Gene Products, RNA; Gestational Age; Glia; Glial Cells; Goals; Guidelines; HIV Dementia; HIV associated dementia; HIV-1; HIV-1 associated dementia; HIV-1 dementia; HIV-Associated Cognitive Motor Complex; HIV-I; HIV-related dementia; HIV1; Hepatitis B; Hepatitis B Infection; Hortega cell; Housing; Human; Human immunodeficiency virus 1; Human, Adult; Human, General; IHC; Idiopathic Parkinson Disease; Immune; Immunity; Immunodeficiency Virus Type 1, Human; Immunohistochemistry; Immunohistochemistry Staining Method; Individual; Infant, Newborn; Inflammatory; Infrastructure; Investigation; Investigators; Kolliker's reticulum; Laboratories; Letters; Leukapheresis; Leukocytapheresis; Leukocytes; Lewy Body Disease; Lewy Body Disease, Cortical; Lewy Body Parkinson Disease; Lewy Body Type Senile Dementia; Link; Liquid substance; Liver; Lymphocyte; Lymphocytic; MS (Multiple Sclerosis); Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow leukocyte; Marrow monocyte; Measures; Medical center; Methods and Techniques; Methods, Other; Mice; Microglia; Molecular Genetic Abnormality; Mononuclear; Mother Cells; Multiple Sclerosis; Murine; Mus; Nebraska; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous; Nervous System Diseases; Nervous System, Brain; Neural Cell; Neural Stem Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neuroglia; Neuroglial Cells; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurologic Disorders; Neurological Disorders; Neuron Degeneration; Neurons; Neurovirology; Newborn Infant; Newborns; Non-neuronal cell; PBL; Paraffin Tissue; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsons disease; Pathology; Pathway interactions; Patients; Pediatrics; Peripheral Blood Lymphocyte; Personal Satisfaction; Phagocytes; Phagocytic Cell; Primary Parkinsonism; Primary Senile Degenerative Dementia; Principal Investigator; Procedures; Process; Progenitor Cells; Programs (PT); Programs [Publication Type]; Proteins; Protocol; Protocols documentation; Publishing; Quality Control; RNA; RNA, Non-Polyadenylated; Recovery; Research; Research Infrastructure; Research Personnel; Research Resources; Research Specimen; Researchers; Resources; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Leukocytes; Reticuloendothelial System, Spleen; Ribonucleic Acid; Sampling; Sclerosis, Disseminated; Severity of illness; Specimen; Spleen; Stem cells; Stroke; Subcellular Process; Supervision; System; System, LOINC Axis 4; Techniques; Therapeutic; Therapeutic Leukopheresis; Time; Tissue, Paraffin; Tissues; Tissues, Fetal; Universities; Vascular Accident, Brain; Viral Hepatitis B; Washington; Week; White Blood Cells; White Cell; Work; adult human (21+); amebocyte; balance; balance function; base; body system, hepatic; brain attack; brain control; brain tissue; cell type; cerebral vascular accident; dementia of the Alzheimer type; disease severity; disease/disorder; experiment; experimental research; experimental study; fetal; fetus tissue; fluid; gene product; gitter cell; human T cell leukemia virus III; human T lymphotropic virus III; human disease; human tissue; insular sclerosis; liquid; lymph cell; macrophage; mesoglia; microbial; microglial cell; microgliocyte; mind control; monocyte; nano formulation; nanoformulation; necropsy; nerve cement; nerve stem cell; nervous system disorder; neural; neural degeneration; neural progenitor cells; neuroAIDS; neurodegeneration; neurodegenerative illness; neurological disease; neuronal; neuronal degeneration; neuronal progenitor; neuronal progenitor cells; newborn human (0-6 weeks); organ system, hepatic; pathway; perivascular glial cell; postmortem; primary degenerative dementia; programs; pup; relating to nervous system; research study; senile dementia of the Alzheimer type; serum hepatitis; spinal fluid; stroke; well-being; white blood cell; white blood corpuscle
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0.961 |
2009 — 2010 |
Ikezu, Tsuneya |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Anti-Inflammatory Regulation of Beta-Amyloidosis @ Boston University Medical Campus
DESCRIPTION (provided by applicant): The over-arching goal of this project is to determine the regulatory role of anti-inflammatory molecules on neuroinflammatory activities and beta-amyloidosis (A[unreadable] aggregation and deposition in brain) in rodent models of Alzheimer's disease (AD). Our previous studies on a double transgenic mouse expressing familial AD mutants of [unreadable]-amyloid precursor protein (APP) and glial fibrillar acidic protein promoter-driven murine CCL2 and APP transgenic mice lacking interferon-? receptor type I demonstrated that chemokines and pro-inflammatory cytokines are critically involved in progression of beta-amyloidosis and microgliosis in brain. Accordingly, glatiramer acetate immunization, a known anti-inflammatory therapy, reduced beta-amyloidosis, enhanced neurogenesis, and improved cognitive function in APP mice. In addition, specific anti-inflammatory cytokines (interleukin-4;IL-4, IL-10, among others) can directly induce anti-inflammatory and neuroprotective phenotype of microglia. Thus, we hypothesize that anti-inflammatory cytokines (IL-4 or IL-10, among others) may induce suppression of neuroinflammation and beta-amyloidosis-related cognitive dysfunction in vivo. Our preliminary studies support this hypothesis, since chronic expression of neutralizing CCL2 mutant (7ND, lacking the first 7 amino acid sequence) suppresses microgliosis and A[unreadable] oligomer accumulation, and improves cognitive function in a double transgenic mice (APP/PS1) expressing APP and presenilin-1 (PS1). Using adeno-associated virus (AAV)-mediated gene delivery system for expressing IL-4, IL-10, 7ND in APP/PS1 mice at pre- and post- symptomatic stages of memory dysfunction, we will ask the following questions: 1) Does 7ND, IL-4, or IL-10 suppress astro/microgliosis? If so, is it restricted to hippocampal region or both in cortex and hippocampus?;2) Does IL-4 or IL-10 induce dendritic-like (CD11c+) microglia? If so, is it neuroprotective?;3) Does IL-4 or IL- 10 induce inflammation regulatory molecules (CD200, CD200R)?;4) Does IL-4 or IL-10 reduce beta- amyloidosis? If so, is it specific to compact plaques, diffuse plaques, or A[unreadable] oligomers?;5) Does IL-4 or IL-10 enhance neurogenesis? If so, is it accompanied with enhanced newly synthesized neurons or astrocytes? 6) Does IL-4 or IL-10 enhance synaptogenesis? If so, is it specific to presynaptic or postsynaptic molecules?;and 7) Does 7ND, IL-4 or IL-10 enhance memory formation after injection of lower doses of AAV? If so, is it effective in both pre-symptomatic and post-symptomatic stages? This proposal is significant, since to the best of our knowledge, therapeutic efficacy of 7ND, IL-4 or IL-10 gene delivery has never been tested in APP or APP/PS1 mice in vivo. These approaches may have significant implication for immunotherapy of AD and other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a leading neurological disease that affects more than 4 million people in the US, who are left without effective therapy. Using the established the genetically engineered mouse model of AD (APP/PS1 mice), we will characterize the beneficial effect of anti-inflammatory cytokines (interleukin-4 and 10) and neutralizing chemokine mutant (for CCL2), on beta-amyloidosis and cognitive function inAPP/PS1 mice. These approaches may have therapeutic implication for AD and other neurodegenerative diseases.
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1 |
2009 — 2010 |
Ikezu, Tsuneya |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Vivo Reconstitution Models For Neuroaids and Beta-Amyloidosis @ Boston University Medical Campus
Anti-retroviral therapy (ART) for human immunodeficiency virus (HIV)-1 infection has prolonged and improved quality and longevity of life. Nonetheless, disease morbidities associated with HIV abound, including cognitive dysfunction (HIV associated dementia, HAD, and minor cognitive movement disorders, MCMD, among others) seen during the later stages of the disease. Thus, as infected people live well into their 60's and beyond they will more commonly face the ravages of neurodegenerative diseases. Currently, it is poorly understood how diseases such as Alzheimer's disease (AD) will be affected by chronic viral infection and how chronic viral infection will alter the tempo and progression of AD. We hypothesize that chronic neuroinflammation mediated by virus-infected mononuclear phagocytes (MP;perivascular macrophages and microglia) can accelerate the onset of AD. We propose developing animal models of beta-amyloidosis in HIV infected brains. We will specifically focus on the role of HIV-1 and neuroinflammation mediators, such as pro-inflammatory cytokines and chemokines, on Aj3 production from neurons and astrocytes, Aj3 degradation by microglia, and Aj3 oligomer formation and deposition in the brain. The study is significant. since we can evaluate the effect of HIV-1-infected microglia on AD pathogenesis. The animal models will be studied by multifaceted analysis to characterize the disease pathogenesis, including neuroinflammation, Aj3-related neuropathology, j3-amyloid precursor protein (APP) processing and aggregation, and Aj3 degrading enzyme cascade. Two specific aims are proposed in this grant application. 1) To investigate the putative roles played by chronic HIV-1 infection on Aj3 synthesis and metabolism in human monocyte-derived macrophages (MDM);2) To characterize the role of persistent viral infection on beta-amyloidosis in severely compromised immunodeficiency mice expressing transgenic APP intracranially reconstituted with HIV-infected human MDM. We will specifically focus on the effect of viral proteins and pro-inflammatory cytokines, and intracellular signaling on regulation of Aj3 synthesis and clearance in two experimental paradigms. The study is significant in developing a preclinical model and elucidating the disease mechanism for early on set of AD in chronic AIDS patients, which will be useful for their prognosis, prevention, and therapy.
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1 |
2016 |
Ikezu, Tsuneya |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Exosome-Mediated Propagation of Pathogenic Tau Protein @ Boston University Medical Campus
Alzheimer's disease (AD) is the most common cause of dementia, currently affecting over 5.3 million Americans, yet lacks an effective therapy. Neurofibrillary tangles are a hallmark of AD and primarily consist of phosphorylated tau protein aggregates. Suppressing the spread of tau during the pre-symptomatic stage will potentially provide a novel preventive therapeutic approach to AD. However, the molecular and cellular mechanism of the synaptic propagation of tau is largely unknown. Exosomes are thought to be important vehicles for the spread of tau; the presence of tau proteins in the exosome fraction of cerebrospinal fluid in AD patients provides strong evidence that this mechanism is an important aspect of the pathophysiology of AD in humans. We hypothesize that microglia apposed to synapses facilitate the spread of tau via phagocytosis and secretion of tau in exosomes, and that amyloid deposition as seen in the AD brain enhances the propagation of tau through microglial activation and co-secretion of inflammatory cytokines and tau protein. Our recent studycogently demonstrate that microglia efficiently phagocytize tau aggregates and then transfer them to neurons via exosomes (Asai H et al, Nat Neurosci 2015). Our work will be powered by novel mouse models that recapitulates tau propagation: The stereotactic injection of an adeno-associated viral vector expressing neuron-specific P301L tau into the medial entorhinal cortex shows that inhibition of exosome synthesis or depletion of microglia dramatically reduces tau propagation to the dentate gyrus in vivo. To support this evidence, we showed that stereotactic injection of tau-containing exosomes from microglia successfully spread tau into dentate granular cells of dentate gyrus in wild type mice. This approach will enable us to model tau propagation using exosomes isolated from human brain tissues and non-transgenic mice. This project will focus on characterizing the role of exosomal secretion in the propagation of tau along anatomically connected neural networks using these novel mouse models with three specific aims: 1) To characterize the composition and propagation property of exosomal tau isolated from human AD brain and its potential for the propagation, 2) To determine microglia or other cell types account for exosome secretion for tau propagation, and 3) To determine how exosomal tau propagation induces neurophysiological and morphological abnormality in novel tau propagation mouse models in vivo. We anticipate that the results obtained from this proposal will lead to an entirely novel paradigm for delaying the progression of disease in AD and other tauopathies, such as frontotemporal dementia and chronic traumatic encephalopathy. Additionally, the proposed mouse models will have a wider application, including synucleinopathies (Parkinson's disease and Lewy body dementia) and prion diseases, since ?-synuclein and prion also spreads via exosomes.
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1 |
2017 |
Hook, Vivian Y. H (co-PI) [⬀] Ikezu, Tsuneya Rissman, Robert A [⬀] |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Biogenesis of Exosomes, Secretion, and Trafficking in Alzheimer's Disease @ University of California San Diego
PROJECT SUMMARY/ABSTRACT This application directly responds to the objective of RFA-AG-17-051. We have recently reported a positive correlation of the levels of pathogenic phosphorylated microtubule-associated protein tau (p-tau) in plasma- derived neuronal exosomes in Alzheimer's disease (AD) patients, suggesting their potential application for biomarkers and their implication as a novel machinery of spreading pathogenic molecules in the brain. However, the exact mechanisms regulating exosome biogenesis and secretion, and their contribution to the propagation of pathogenic molecules are poorly understood. Here we propose comprehensive approaches to delineate the molecular mechanisms that regulate biogenesis, secretion and trafficking of exosomes in different brain cell types (neurons, astrocytes and microglia) in vitro and in vivo. This project will (1) analyze the roles of the ESCRT (endosomal sorting complexes required for transport)-dependent pathway, combined with the ESCRT-independent (lipid- and tetraspanin-dependent pathways), for exosome biogenesis and secretion in murine and human neuronal cell types, (2) define the molecular machinery components responsible for exosome biogenesis and secretion in human induced pluripotent stem cells (hiPSCs) derived from AD patients, (3) characterize the exosome protein interactions with target cells for propagation using AD hiPSCs, and (4) characterize the trafficking of exosomes originated from specific neuronal and glial cell types in the central nervous system to periphery. We have assembled a group of collaborative investigators with established programs in cell biology, exosome biology, proteomics and animal models of neurodegenerative disorders. The proposed research work will develop a new understanding of exosomal biology and detailed functions of exosomes in progression of AD pathology. The findings gained from this research project will have a potential to discover new molecular targets for suppression of the disease spread via exosomes, and also address the National Alzheimer's Project Act plan to accelerate basic research toward development of AD therapeutics.
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0.961 |
2020 |
Ikezu, Tsuneya |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting Emerging P2rx7 Signaling Pathways in Animal Models of Alzheimer's Disease @ Boston University Medical Campus
Neurofibrillary tangles, composed of intracellular aggregates of hyperphosphorylated tau protein are by far the most correlated pathology with clinical symptoms of Alzheimer disease (AD). Emerging evidence suggests that extracellular vesicles (EVs), such as exosomes and microvesicles, transfer pathological tau protein between cells as vehicles, and propagate tau pathology in different brain regions. It is urgently important to find the molecular basis of brain-derived EV, which critically regulates the transport and uptake of pathogenic tau protein between neuronal cells and aggregation of tau protein in recipient neurons. The purpose of the current application is to delineate the effect of P2RX7, a purinergic receptor, on EV- mediated tau propagation. Our preliminary data have shown that suppressing microglial EV secretion by GSK 1482160 compound, a specific inhibitor of the P2RX7, dramatically reduces tau aggregation in CA1 and CA3 pyramidal neuronal cells and dentate granular cells with P301S tauopathy animal model. Interestingly this coalesces with reduction of exosome-specific ?endosomal sorting complexes required for transport? (ESCRT) EV marker, TSG101, in the same hippocampal regions, suggesting the possible EV trafficking from microglia to hippocampal neurons, which may transfer and seeds misfolded tau and accelerate protein aggregation in receiving neurons. Thus, those data indicate the regulatory mechanism by P2RX7 on EV mediated tau propagation and posit the therapeutic potential of the P2RX7 inhibitor for AD or other tauopathy. We hypothesize that P2RX7 critically regulates the transfer of EVs between microglia and neurons in the hippocampal neurons, thereby facilitate spreading misfolded tau. We will validate the effect of GSK1482160 on tau propagation by recapitulating those findings using P2rx7 deletion in P301S tau mice and adeno-associated virus (AAV)-based tau propagation mouse model. In Aim 1, we will determine the effect of systemic deletion of P2rx7 in P301S mouse. The distribution of EV markers and tau pathology in the hippocampal regions will be evaluated and compared with the findings from GSK1482160-administered P301S mice. In Aim 2, we will determine the effect of P2RX7 on secretion and transfer of EV and EV-associated tau and its aggregation potency in vitro. This will determine which cell type is particularly responsible for P2RX7 regulated tau spread into hippocampal neurons. In Aim 3, we will confirm the cell type, which is selected in Aim 2, for the export of EVs into hippocampal neurons by cell type- specific deletion of P2rx7 or Tsg101, an exosome synthesis molecule, and validate if P2RX7-mediated EV secretion are responsible for tau propagation using AAV-based tau propagation mouse model. Successful completion of this study will enhance our understanding of molecules that mediates secretion of EVs from glia to neurons in vitro and in vivo, and identify novel targets for AD.
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1 |