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Principal Investigator: Eliezer Masliah
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2022
Award: $83,630
Funding agency: National Institute on Aging
The main objective of the Molecular Neuropathology unit (MNU) at Laboratory of Neurogenetics (LNG) is to harness the immune system to better understand the mechanisms of neurodegeneration and to develop therapies for synucleinopathies of the aging population such as DLB, PD and AD. We propose 3 Aims, the first investigating the role of innate immune responses and combinatorial immunotherapy targeting LRRK2, Toll-like receptors, p38, NFAT and the protein aggregates (eg: a-synuclein, Abeta, tau) in PD/DLB; the second assessing downstream pro-inflammatory signaling pathways including MAPK-p38, NFAT and NFkB and the third evaluating the role of aging in T cell mediated adaptive immune cell responses in PD/DLB pathogenesis and for developing immunotherapies for synucleinopathies. During this period, we published 9 manuscripts mostly focusing understanding the pathogenesis of PD/DLB and developing novel pharmacological and immunotherapeutical approaches.
Progress for Aim1. In previous studies we identified several immune receptors that mediate neuroinflammation in synucleinopathies, including Toll-like receptor 2 (TLR2) and have shown which species of a-synuclein bind TLR2 and mediates neuroinflammation. These results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic a-syn transmission, but activation of microglial TLR2 enhances microglial extracellular a-syn clearance. Along these lines we recently published a manuscript (Torres et al Neurobiol of Dis 2022) characterizing in vivo in our a-synuclein transgenic model the relationship between degeneration of interneurons and neuroinflammation in the amygdala. As an extension and given the impact of the COVID19 pandemic and potential role of SARS-CoV2 in AD/ADRD we investigated (in collaboration with the Nath laboratory) inflammation in the brains of COVID19 patients with evidence of neurological involvement, we found increased a-synuclein accumulation in axons and glial cells as well as astrocytic activation and T cell trafficking in affected CNS areas. Moreover, preliminary studies indicate that the SARS-CoV2 envelope protein might interact with TLR2 and play a role in inflammation and a-synuclein driven pathology, we published a manuscript addressing this possibility (Szabo et al Exp Mol Med 2022). Finally, this year in collaborative projects with academia we made considerable progress developing novel ADRD immunotherapies that either target 3RTau (Spencer et al Methods Mol Biol 2022) or simultaneously target multiple epitopes of a-synuclein. For Tau we developed a novel brain penetrating single chain antibody packed in a viral vector that can be applied peripherally. For a-synuclein, we used the MultiTEP based DNA vaccine technology which is an approach especially useful for the elderly with immunosenescence. All vaccines induced high titers of antibodies specific to a-synuclein that significantly reduced PD/DLB-like pathology in mice. The most significant effects were observed in mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. We published two recent studies (Kim et al Vaccines 2022 and Zagorski et al Int J Mol Scie 2022).
Progress for Aim 2. In collaboration with the Cookson group (Kim et al Science TM 2020) showed that LRRK2 plays a critical role in the activation of microglia by extracellular a-synuclein. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies. Next, we investigated the hypothesis that blocking NFATc2 translocation might ameliorate a-synuclein-mediated microglial neurotoxicity. Preliminary studies identified a novel peptide compound (11r VIVIT) that when administered peripherally into -syn tg mice reduced neuroinflammation, restores NFATc2 cytoplasmic localization and ameliorates behavioral deficits. We are currently expanding these studies to include detailed characterization of microglial transcriptomic, phenotypic profiling (M1 vs M2), neuropathological and functional examination. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies. This paper is currently under preparation for submission. The next step is to investigate the immunomodulatory role of p38 inhibitors in models of synucleinopathy. We have previously shown that the synaptic MAPK p38-gamma plays a role synaptotoxicity in DLB/PD, while p38-alpha plays a role in neuroinflammation. We treated our animal models of DLB/PD with a p38 inhibitor that crosses the blood brain barrier and evaluated the effects on synaptic function and neuroinflammation. The results of this study were presented at the intramural NIA retreat and at SfN and a manuscript was recently submitted to Science TM.
Progress for Aim 3. In collaboration with the Sen laboratory we showed that T cell infiltration with potential participation of NKT cells play an important role in DLB/PD. Next, we explored the role of aging in the pathogenesis of PD/DLB by analyzing, behavior, neuropathology and transcriptomics and immune responses in young and aged wildtype mice that received intrastriatal injections with a-synuclein preformed fibrils (pff). We found that aged mice showed more extensive accumulation of a-synuclein and behavioral deficits that was associated with greater infiltration of T cells and microgliosis. Distinct inflammatory patterns of gene expression in microglia showed that a-synuclein pff-induced genes networks in young mice (eg: CSF2, TNF, IL1b, IL6) that overlaps with genes differentially expressed in microglia in the aged mice. These results indicate that the aged and more inflamed brain micro-environment directly influences the disease outcome of pathological accumulation of a-syn in age-related chronic diseases such as DLB and PD. This manuscript was recently re-submitted to Molecular Neurodegeneration. Other experiments underway includes investigating the effects of aging and deleting microglia with the PLX3387 (a compound that targets CSF1R) on synucleinopathies in DLB/PD models.We are also investigating the effects of aging and inflammation in models where T cells and microglia are deleted or where CSF1 and CSF2 are modulated, manuscripts for all these studies are under preparation. Other collaborations at LNG are with Drs. Cookson, Singleton, Traynor and Scholz on the genetic architecture of FTD, DLB and MSA by providing expert neuropathological assessment, animal models and human postmorten brain tissues.
In addition to the collaborations with LNG, we have been collaborating with the laboratory of Dr. Avi Nath at NINDS investigating the neuropathology of COVID19 that resulted on a recent publication on the microvascular alterations in NeuroCOVID (Nath et al NEJM 2021) and with Dr. Robert Tycho on modeling mechanisms of a-syn protein aggregation.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AD dementia><AD related dementia><ADRD><Academia><Address><Affect><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer related dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Alzheimers disease><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><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><Animals><Antibodies><Antibody titer measurement><Antigenic Determinants><Apo-E><ApoE><Apolipoprotein E><Area><Astrocytes><Astrocytus><Astroglia><Axon><Aβ><B blood cells><B cell><B cells><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><B-Cells><B-Lymphocytes><B-cell><BSF-2 Gene><BSF2 Gene><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavioral><Beta-2 Gene Interferon><Binding><Binding Determinants><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Nervous System><CD115><CD115 Gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 pandemic affected><COVID-19 pandemic consequence><COVID-19 pandemic effects><COVID-19 pandemic impact><COVID-19 pandemic impacted><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19><COVID19 patient><COVID19 positive patient><COVID19 virus><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><CSF1><CSF1 gene><CSF1R><CSF1R gene><CSF2><CSF2 gene><CSFMR><CV-19><CV19><Cachectin><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Senescence><Cell Signaling><Cell model><Cells><Cellular Aging><Cellular Senescence><Cellular model><ChIP Sequencing><ChIP-seq><Chronic Disease><Chronic Illness><CoV-2><CoV2><Collaborations><Colony Stimulating Factor 1 Receptor Gene><Combination immunotherapy><Connector Neuron><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><DNA Damage><DNA Injury><DNA Vaccines><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dementia with Lewy Bodies><Disease Outcome><Disease model><ERK6><ERK6 Protein><Elderly><Encephalon><Envelope Protein><Epitopes><Expression Signature><Extracellular Signal-Regulated Kinase 6><Extracellular Signal-Regulated Kinase Gene><GEM model><GEMM model><Gamma-delta T cells><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetically Engineered Mouse><Glia><Glial Cells><Goals><HSF Gene><Hemato-Encephalic Barrier><Hepatocyte Stimulatory Factor Gene><Hortega cell><Human><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-6 Gene><IL6><IL6 gene><IMiD><Immune><Immune Modulation Therapy><Immune infiltrates><Immune mediated therapy><Immune modulatory therapeutic><Immune response><Immune system><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunologic Receptors><Immunological Receptors><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunomodulators><Immunotherapeutic agent><Immunotherapy><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Injections><Innate Immune Response><Innate Immunity><Intercalary Neuron><Intercalated Neurons><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-6 Gene><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Kinases><Kolliker's reticulum><LRRK2><LRRK2 gene><LRRK2 leucine-rich repeat kinase 2 gene><LRRK2 protein><Laboratories><MAP Kinase 12><MAP Kinase Gene><MAPK><MAPK12><MAPK12 Mitogen-Activated Protein Kinase><MAPK12 gene><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><MCSF><MGC31930><MT-bound tau><Macrophage-Derived TNF><Manuscripts><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Methods><Mice><Mice Mammals><Microglia><Mitogen-Activated Protein Kinase 12><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mouse Strains><Murine><Mus><Mxi2><NAC precursor><NF-AT><NF-AT proteins><NF-kB><NF-kappa B><NF-kappaB><NFAT proteins><NFAT-1><NFATC proteins><NFKB><NINDS><Naked DNA Vaccines><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Native Immunity><Natural Immunity><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neuroimmune><Neuroimmune system><Neurologic><Neurologic Degenerative Conditions><Neurological><Neuron Degeneration><Neurons><Non-Specific Immunity><Non-neuronal cell><Nonneuronal cell><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nuclear Translocation><P38Gamma><PARK1 protein><PARK4 protein><PARK8 protein><PD with dementia><Paper><Paralysis Agitans><Parkinson><Parkinson Dementia><Parkinson Disease><Parkinson Disease dementia><Parkinson Disease with dementia><Parkinson disease 8 protein><Parkinson's Dementia><Parkinson's Disease dementia><Parkinson's disease><Parkinson's disease with dementia><Parkinsons disease><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Peptides><Peripheral><Pharmacology><Phenotype><Phosphotransferase Gene><Phosphotransferases><Play><Preparation><Primary Parkinsonism><Primary Senile Degenerative Dementia><Publications><Publishing><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recombinant DNA Vaccines><Replicative Senescence><Research><Role><SAP Kinase-3><SAPK-3><SAPK2A><SAPK3><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SNCA><SNCA protein><Science><Scientific Publication><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress-Activated Protein Kinase 2A><Stress-Activated Protein Kinase 3><Stress-Activated Protein Kinase-3><Synapses><Synaptic><System><T cell infiltration><T cell response><T cell tumor trafficking><T-Cells><T-Lymphocyte><TAR DNA-binding protein 43><TDP-43><TDP43><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Therapeutic><Therapeutic Effect><Toll-Like Receptor 2><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Transgenic Model><Transmission><Transphosphorylases><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-infiltrating immune cells><Vaccinated><Vaccines><Viral Vector><Wild Type Mouse><Wuhan coronavirus><a beta peptide><a-syn><a-synuclein><abeta><adaptive immunity><advanced age><age dependent><age effect><age related><aged><aged population><aging effect><aging population><allergic/immunologic body system><allergic/immunologic organ system><alpha synuclein><alphaSP22><amygdaloid nuclear complex><amyloid beta><amyloid-b protein><antibody titering><astrocytic glia><asyn><base><beta amyloid fibril><biological signal transduction><bloodbrain barrier><brain tissue><c-FMS><c-fms Genes><c-fms Proto-Oncogenes><cell type><chromatin immunoprecipitation-sequencing><chronic disorder><combinatorial><combinatorial immunotherapy><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 pandemic consequence><coronavirus disease 2019 pandemic impact><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytoplasmic nuclear factor of activated T-cells><dardarin><dardarin gene><dardarin protein><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><dementia in PD><dementia in Parkinson disease><dementia of the Alzheimer type><develop therapy><differential expression><differentially expressed><disorder model><dual immunotherapy><effects following the COVID-19 pandemic><elders><env Antigens><env Gene Products><env Polyproteins><env Protein><experiment><experimental research><experimental study><extracellular><gene expression pattern><gene expression signature><gene network><genetic architecture><genetically engineered mouse model><genetically engineered murine model><geriatric><gitter cell><hCoV19><host response><immune cell infiltrate><immune drugs><immune infiltration><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulating therapies><immune modulation><immune modulators><immune modulatory agents><immune modulatory drugs><immune modulatory therapies><immune receptor><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-modulation treatment><immuno therapy><immunologic preparation><immunologic reactivity control><immunologic therapeutics><immunomodulating agents><immunomodulation therapy><immunomodulation treatment><immunomodulatory><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><immunoresponse><immunosenescence><immunotherapeutics><immunotherapy agent><in vitro Model><in vivo><in vivo Model><inhibitor><insoluble aggregate><intervention development><intratumoral immune cell><kappa B Enhancer Binding Protein><late life><later life><leucine-rich repeat kinase 2><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><model of animal><model organism><nCoV2><nerve cement><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurogenetics><neuroinflammation><neuroinflammatory><neurological degeneration><neuron toxicity><neuronal><neuronal degeneration><neuronal toxicity><neuropathology><neurotoxic><neurotoxicity><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><nuclear factor kappa beta><nuclear factors of activated T-cells><older adult><older person><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><p38gamma MAP Kinase><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><perivascular glial cell><population aging><primary degenerative dementia><protein TDP-43><protein TDP43><protein aggregate><protein aggregation><protein homeostasis><proteostasis><receptor><response><scRNA-seq><senile dementia of the Alzheimer type><senior citizen><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><sex><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule><social role><soluble amyloid precursor protein><synapse><synapse function><synaptic function><synucleinopathy><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tau><tau Proteins><tau factor><therapeutic target><therapy development><thymus derived lymphocyte><trafficking><transcription factor><transcription factor NF-AT><transcriptional differences><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomics><transgenic trait><transmission process><treatment development><tumor immune cell><wildtype mouse><α-syn><α-synuclein><γδ T cells><γδT cells><τ Proteins>