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Principal Investigator: Eliezer Masliah
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2021
Award: $57,874
Funding agency: National Institute on Aging
The main objective of the Molecular Neuropathology section (MNS) 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 over 20 manuscripts mostly focusing understanding the pathogenesis of PD/DLB and developing novel pharmacological and immunotherapeutical approaches.
Progress for Aim1. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of -syn aggregates varies from study to study, and how different -syn aggregate species interact with innate immune receptors has yet to be addressed. We recently published a new study (Kim et al, Exp Mol Med 2021), where we investigated whether innate immune receptors can facilitate the uptake of different species of a-syn aggregates. We reported that stimulation of TLR2 in vitro accelerated a-syn fibril uptake in neurons and glia while delaying the degradation of a-syn in neurons and astrocytes. Internalized a-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular a-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a DLB/PD mouse models increased the density of Lewy-body-like pathology and induced morphological changes in microglia. Together, 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. The next steps will investigate the effects of aging and deleting microglia with the PLX3387 (a compound that targets CSF1R) on synucleinopathies in DLB/PD models.
Progress for Aim 2. In collaboration with the Cookson group we are investigating the cross talk between TLR2 and LRRK2 and downstream signaling involving NFATC leading to neurodegeneration and inflammation in PD/DLB. We recently published a manuscript (Kim et al Science TM 2020) showing that LRRK2) plays a critical role in the activation of microglia by extracellular a-synuclein. Exposure to a-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished a-synuclein-mediated microglial neurotoxicity via lowering of tumor necrosis factor- and interleukin-6 expression in mouse cultures. 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). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies. The next steps include developing specific antibodies that recognize pNFAT phosphorylated by activation of the TLR2-LRKK2 pathway and to test the effects of compounds and genetic manipulations targeting NFAT.
Progress for Aim 3. In collaboration with the Sen laboratory we recently published (Iba et al J Neuroinflammation 2020) one of the first studies in the field demonstrating that neuroinflammation in synucleinopathies involves considerable T cell infiltration with potential participation of NKT cells. 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-syn preformed fibrils (pff). We found that aged mice showed more extensive accumulation of a-syn 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-syn 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 is under revision in Nature Aging. Along these lines, in another recent publication (Roshanbin et al Neurobiology of Dis 2021) we found that in our -syn transgenic model of DLB/PD there is and age dependent increase in a-syn oligomers and motor dysfunction. Taken together, our data indicate that a-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg -syn mouse model. The next steps will be to investigate the effects of aging and inflammation in models where T cells and microglia are deleted or where CSF1 and CSF2 are modulated. 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), we plan to continue these studies and investigate the role of SARS-CoV2 at accelerating the pathology of AD/ADRD in particular inflammation and protein aggregation
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AD dementia><AD pathology><AD related dementia><ADRD><Adaptive Immune System><Address><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 pathology><Alzheimer's disease related dementia><Alzheimer's pathology><Alzheimers Dementia><Alzheimers disease><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><Astrocytes><Astrocytus><Astroglia><Attenuated><Aβ><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor Gene><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor 2 Gene><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF-2 Gene><BSF2><BSF2 Gene><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavioral><Beta-2 Gene Interferon><Brain><Brain Nervous System><Brain Pathology><CD115><CD115 Gene><COVID-19><COVID-19 virus><COVID19><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 Body><Cell Communication and Signaling><Cell Signaling><Cell model><Cells><Cellular model><ChIP Sequencing><ChIP-seq><Chronic Disease><Chronic Illness><CoV-2><CoV2><Collaborations><Colony Stimulating Factor 1 Receptor Gene><Combination immunotherapy><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Data><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dementia with Lewy Bodies><Development><Disease Outcome><Disease model><Encephalon><Exposure to><Expression Signature><Extracellular Signal-Regulated Kinase Gene><GEM model><Gamma-delta T cells><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetically Engineered Mouse><Glia><Glial Cells><Goals><HPGF><HSF Gene><Hepatocyte Stimulatory Factor Gene><Hepatocyte-Stimulating Factor><Homolog of Drosophila TOLL><Hortega cell><Human><Hybridoma Growth Factor><Hybridoma Growth Factor Gene><IFN-beta 2><IFNB2><IFNB2 Gene><IL-6><IL-6 Gene><IL6><IL6 Protein><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><Injections><Innate Immune Response><Innate Immunity><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-6><Interleukin-6 Gene><Intracellular Communication and Signaling><Kinetics><Kolliker's reticulum><LRRK2><LRRK2 gene><LRRK2 leucine-rich repeat kinase 2 gene><LRRK2 protein><Laboratories><Lewy Bodies><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><MCSF><MGC31930><MGI-2><MT-bound tau><Macrophage-Derived TNF><Manuscripts><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Mice><Mice Mammals><Microglia><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Morphology><Motor><Mouse Strains><Murine><Mus><Mxi2><Myeloid Differentiation-Inducing Protein><NAC precursor><NF-AT><NF-AT proteins><NF-kB><NF-kappa B><NF-kappaB><NFAT proteins><NFAT-1><NFATC proteins><NFKB><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Native Immunity><Natural Immunity><Nature><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurobiology><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neuroimmune><Neuroimmune system><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-Specific Immunity><Non-neuronal cell><Nonneuronal cell><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nuclear Translocation><PARK1 protein><PARK4 protein><PARK8 protein><PD with dementia><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><Patients><Pharmacology><Phosphorylation><Plasmacytoma Growth Factor><Play><Predisposition gene><Primary Parkinsonism><Primary Senile Degenerative Dementia><Protein Phosphorylation><Proteins><Publications><Publishing><RNA Seq><RNA sequencing><RNAseq><Reporting><Research><Role><SAPK2A><SARS corona virus 2><SARS-CoV-2><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 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><Susceptibility Gene><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><TLR4><TLR4 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TREM2><TREM2 gene><Testing><Therapeutic><Therapeutic Effect><Toll Homologue><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><Triggering Receptor Expressed on Myeloid Cells 2><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-infiltrating immune cells><Up-Regulation><Upregulation><Wild Type Mouse><Wuhan coronavirus><a beta peptide><a-syn><a-synuclein><abeta><acquired immune system><adaptive immunity><age dependent><age effect><age related><aged><aged population><aging effect><aging population><allergic/immunologic body system><allergic/immunologic organ system><alpha synuclein><alphaSP22><amyloid beta><amyloid-b protein><astrocytic glia><beta amyloid fibril><biological signal transduction><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 virus><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><density><develop therapy><developmental><differential expression><differentially expressed><disorder model><dual immunotherapy><experiment><experimental research><experimental study><extracellular><gene expression pattern><gene expression signature><gene manipulation><genetic architecture><genetic manipulation><genetically engineered mouse model><genetically engineered murine model><genetically manipulate><genetically perturb><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><immunotherapeutics><immunotherapy agent><in vitro Model><in vivo Model><inhibitor><inhibitor/antagonist><insoluble aggregate><interferon beta 2><intervention development><intratumoral immune cell><kappa B Enhancer Binding Protein><leucine-rich repeat kinase 2><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><model of animal><model organism><motor disease><motor disorder><motor dysfunction><mouse model><murine model><nCoV2><nerve cement><neural degeneration><neurobiological><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><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pathway><perivascular glial cell><population aging><predisposing gene><primary degenerative dementia><protein TDP-43><protein TDP43><protein aggregate><protein aggregation><response><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><social role><soluble amyloid precursor protein><susceptibility allele><susceptibility locus><susceptibility variant><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><toll-like receptor 4><transcription factor><transcription factor NF-AT><transcriptional differences><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomics><transgenic trait><transmission process><treatment development><tumor immune cell><uptake><wildtype mouse><α-syn><α-synuclein><γδ T cells><γδT cells><τ Proteins>