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Principal Investigator: Alexis Marie Johnson
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $38,001
Funding agency: National Institute on Aging
PROJECT ABSTRACT/SUMMARY:
Tauopathies are a broad, prevalent, and lethal class of neurodegenerative disorders that affect up to 7 million
Americans. There is a tremendous need for improved therapeutic strategies to treat the conditions that fall
under this category, namely Alzheimer's disease (AD) and frontotemporal dementia (FTD). Recent work has
begun to uncover critical roles for microglia, which are brain-resident macrophages, and the function of distinct
microglial immune receptors in AD and FTD progression. Several immunoreceptor tyrosine-based activation
and inhibitory motif-containing receptors, including TREM2, CD22, and CD33, have been identified in genome-
wide association studies or animal studies. These receptors have been shown to have a critical impact on the
progression of neurodegenerative diseases in AD. Interestingly, these receptors converge downstream at
spleen tyrosine kinase (SYK). Recent findings from our lab have uncovered SYK's beneficial role in controlling
disease outcomes in an amyloid beta (Aβ) amyloidosis mouse model of AD, where it was shown to be a central
orchestrator of microglial activation. Given these insights, it is crucial to explore SYK's role in other types of
degeneration, such as that caused by pathogenically phosphorylated tau (p-tau). In preliminary studies, I found
that genetic ablation of microglia Syk in the tau-mediated PS19 mouse model of AD/FTD leads to a decreased
p-tau burden, improved cognitive function, and maintenance of homeostatic microglia signature. Given these
results, coupled with the general body of literature which concludes that aberrant innate immune activity is
detrimental to tauopathy progression and drives increased tau hyperphosphorylation, I hypothesize that
removal of SYK signaling, and subsequent dampening of microglial activation, will blunt tau-mediated
neurological disease by promoting neuroprotective and anti-inflammatory functions in microglia. In Aim 1, I will
investigate a microglial-specific role for SYK in modulating tauopathy and associated neurodegeneration. In
Aim 2, I will study the mechanisms by which the loss of SYK specifically affects microglial activation to provide
further understanding of the role of SYK signaling in neurodegeneration. Finally, in Aim 3, I will evaluate if
genetically deleting microglial Syk offers an effective strategy to limit disease at a time point when PS19 mice
exhibit signs of tau pathology and cognitive deficits. Completion of the proposed studies will break new ground
in our understanding of the intracellular molecular mediators (i.e. SYK) that orchestrate immune responses in
primary tauopathy and will further reveal how microglia activation contributes to neurodegenerative disease
etiology. Moreover, this work is of potential translational significance as it will interrogate the therapeutic
efficacy of SYK-inhibiting treatment in limiting the progression of AD and FTD.
Terms: <AD dementia><AD model><AD pathology><Ablation><Abscission><Affect><Age Months><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Amentia><American><Ammon Horn><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyloidosis><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Area><Autophagocytosis><Aβ><B-Cell Antigen CD22><B3 antigen><Brain><Brain Nervous System><CD22><CD22 antigen><CD22 gene><CNS Nervous System><Categories><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Expansion><Cellular Growth><Central Nervous System><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Cornu Ammonis><Coupled><Degenerative Neurologic Disorders><Dementia><Disease><Disease Outcome><Disease Progression><Disease associated microglia><Disorder><Disturbance in cognition><Encephalon><Environment><Etiology><Excision><Exhibits><Expression Signature><Extirpation><Frontal Temporal Dementia><Frontotemporal Dementia><Future><GWA study><GWAS><Gene Expression Profile><Genetic><Gliosis><Goals><Hippocampus><Hortega cell><Immune><Immune response><Immune signaling><Immunes><Immunologic Receptors><Immunological Receptors><Immunological response><Immunomodulation><Impaired cognition><Infection><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Kinases><Link><Literature><Lobar Atrophy of the Brain><MT-bound tau><Macrophage><Maintenance><Mediating><Mediator><Mice><Mice Mammals><Microglia><Molecular><Murine><Mus><Mφ><Nerve Degeneration><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neuritic Plaques><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurofibrillary Tangles><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Onset of illness><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Pattern><Peripheral><Phagocytosis><Phosphotransferase Gene><Phosphotransferases><Pick Disease of the Brain><Pick's Disease><Play><Population><Prevalence><Primary Senile Degenerative Dementia><Production><Receptor Protein><Regulation><Removal><Reporting><Research><Role><SIGLEC2><SYK><SYK gene><Senile Plaques><Severities><Shapes><Sialic Acid-Binding Immunoglobulin-Like Lectin 2><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Sorting><Spleen Tyrosine Kinase><Surgical Removal><TREM2><TREM2 gene><Tauopathies><Testing><Therapeutic><Therapeutic Intervention><Time><Transphosphorylases><Treatment Efficacy><Triggering Receptor Expressed in Myeloid Cells 2><Triggering Receptor Expressed on Myeloid Cells 2><Tyrosine><Tyrosine-Protein Kinase SYK><Weaning><Work><a beta peptide><abeta><abnormally aggregated tau protein><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><alzheimer model><amyloid beta><amyloid beta plaque><amyloid disease><amyloid-b plaque><amyloid-b protein><autophagy><aβ plaques><beta amyloid fibril><biological signal transduction><causation><cell growth><clinical relevance><clinically relevant><cognitive ability><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><cored plaque><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diffuse plaque><disease causation><disease control><disease model><disease onset><disorder control><disorder model><disorder onset><extracellular><filamentous tau inclusion><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><gene expression pattern><gene expression signature><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><gitter cell><glial activation><glial cell activation><hippocampal><host response><hyper-phosphorylated tau><hyperphosphorylated tau><immune modulation><immune receptor><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><innovate><innovation><innovative><insight><intervention efficacy><intervention therapy><interventional strategy><mesoglia><microglial cell><microgliocyte><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mouse model><murine model><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuronal degeneration><neuropathologic><neuropathologic tau><neuropathological><neuropathological tau><neuropathology><neuroprotection><neuroprotective><neurotoxic><p-tau><p-τ><paired helical filament of tau><pathway><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><population aging><post-translational modification of tau><posttranslational modification of tau><primary degenerative dementia><protection pathway><protective pathway><receptor><resection><response><restraint><scRNA-seq><self-aggregate tau><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><soluble amyloid precursor protein><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><therapeutic efficacy><therapeutically effective><therapy efficacy><transcriptional profile><transcriptional signature><translational opportunities><translational potential><whole genome association analysis><whole genome association studies><whole genome association study><τ Proteins><τ aggregation><τ phosphorylation>