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Principal Investigator: EVGENY I ROGAEV
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $828,534
Funding agency: National Institute on Aging
Summary
Molecular-genetic studies have illuminated the primary pathway of Alzheimer’s disease (AD). However, a
relatively long chronic prodromal period of the disease, and the cascade of molecular events underlying the
AD-associated synaptic and neuronal loss and neurodegeneration in the aging brain, have not yet been fully
elucidated. Aging is the most common risk factor contributing to the decline of both the immune system and
brain function.
Recently, we, and others, demonstrated that, surprisingly, the adaptive immune system is involved in
Alzheimer’s disease. As this is a newly emergent field, the molecular mechanisms of interactions between
adaptive immunity and AD remains unknown. We hypothesize that harmful populations of γδT-cells or brain-
infiltrating αβT-cells (CD8+ T-cells) responding to aberrantly expressed antigens in the brain contribute to AD
pathology. In our recent report and in our preliminary data, we found that the depletion of B-cells or T-cells (
CD8+ T cells) in AD model mice reduces AD-associated pathology. Although we, and others, detected the T-
cells in the human and mouse brain, the hypervariable immunogene TCR-repertoires and molecular identities
of populations of T-cells in the brain have not yet been determined. This implies that the origin and functional
connections of adaptive immune and brain cells remain unknown. We have developed and applied highly
sensitive assays to track TCR repertoires in AD patients versus controls. On the other hand, we found highly
increased epigenomic chromatin accessibility and upregulation of adaptive immune response genes (MHC
complex and other genes) in the neuronal and non-neuronal residential cells in the AD brain. We will apply
large-scale, innovative, high-throughput genomic technologies for the analysis of AD-mouse models and a
large collection of clinically characterized brain specimens from both AD and non-demented subjects. We will
conduct a molecular dissection of the neuronal- adaptive immune- genomic axis to identify novel integrative
factors contributing to AD pathogenesis or to the protection of brain neurons in the aging process.
Terms: <AD dementia><AD model><AD pathology><Adaptive Immune System><Aging><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's Disease Pathway><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Animal Disease Models><Antigen Presentation><Antigen Targeting><Antigens><Assay><Attenuated><B blood cells><B cell><B cells><B-Cell Deficiency><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological><Biological Assay><Biological Markers><Brain><Brain Mapping><Brain Nervous System><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Causality><Cell Body><Cell Shape><Cells><Chromatin><Chromosome Mapping><Chronic><Class II Antigens><Class II Major Histocompatibility Antigens><Clinical><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collection><Complex><Data><Degenerative Neurologic Disorders><Disease><Disorder><Dissection><Disturbance in cognition><Elderly><Elements><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Event><Gamma-delta T cells><Gene Expression><Gene Localization><Gene Mapping><Gene Mapping Genetics><Genes><Genetic><Genetic study><Genomic approach><Genomics><Glia><Glial Cells><Goals><Haplotypes><Histocompatibility Antigens Class II><Histocompatibility Complex><Histocompatibility Complices><Hortega cell><Human><I-A Antigen><Ia Antigens><Ia-Like Antigens><Immune><Immune Response Antigens><Immune Response Genes><Immune infiltrates><Immune system><Immune-Response-Associated Antigens><Immunes><Immunogenetics><Impaired cognition><Individual><Infiltration><Inflammation><Ir Gene><Kolliker's reticulum><Link><Linkage Mapping><MHC Class II Molecule><MHC Class II Protein><MHC class II antigen><Major Histocompatibility Complex><Major Histocompatibility Complex Class II><Major Histocompatibility Complex Gene><Major Histocompatibility Complices><Mice><Mice Mammals><Microglia><Modern Man><Molecular><Molecular Genetics><Murine><Mus><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><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-neuronal cell><Nonneuronal cell><Pathogenesis><Pathology><Population><Primary Senile Degenerative Dementia><Process><Property><Public Health><Reporting><Research><Research Specimen><Resolution><Risk Factors><Sampling><Shapes><Specific qualifier value><Specified><Specimen><Synapses><Synaptic><T cell infiltration><T-Cell Depletion><T-Cell Receptor Genes><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-cell receptor repertoire><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TCR repertoire><TcR Genes><Technology><Total Human and Non-Human Gene Mapping><Transgenic Mice><Up-Regulation><Upregulation><acquired immune system><adaptive immune response><adaptive immunity><advanced age><aged brain><aging brain><aging process><alzheimer model><alzheimer risk><antigen-specific T cells><attenuate><attenuates><bio-markers><biologic><biologic marker><biomarker><brain cell><causation><cell type><cognitive dysfunction><cognitive loss><cohort><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease causation><effective therapy><effective treatment><epigenetically><epigenomics><genetic mapping><genome profiling><genomic effort><genomic profiling><genomic strategy><geriatric><gitter cell><global gene expression><global transcription profile><human disease><humoral immunity deficiency><immune cell infiltrate><immunogen><individual heterogeneity><individual variability><individual variation><innovate><innovation><innovative><mesoglia><microglial cell><microgliocyte><mouse model><murine model><nerve cell death><nerve cell loss><nerve cement><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><non-demented><nondemented><novel><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><peripheral blood><perivascular glial cell><primary degenerative dementia><resolutions><senile dementia of the Alzheimer type><senior citizen><synapse><thymus derived lymphocyte><transcriptome><γδ T cells><γδT cells>