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Principal Investigator: David E Kang
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $512,136
Funding agency: National Institute on Aging
Project Summary
Accumulating evidence indicates that the ability to mount an effective Nrf2-mediated gene
expression response to oxidative stress declines during the aging process. In particular, nuclear
but not cytoplasmic Nrf2 is depleted in neurons of AD patients. In animal models, loss of Nrf2
signaling exacerbates amyloid and tau deposition, neuroinflammation, and cognitive deficits,
whereas induction of Nrf2 signaling protects against these phenotypes. While toxic tau
assemblies, oxidative stress, cytoskeletal disruption, and autophagy defects are cardinal features
of tauopathies, including AD, how these cellular brain phenotypes integrate at the molecular level
to produce physiological or pathological responses during tau pathogenesis is unknown. In
addition to the known regulation of the cytoskeleton, mitochondria, and autophagy by SSH1, our
new preliminary studies show that the SSH1 pathway intersects with the Nrf2 to inhibit and titrate
Nrf2 signaling. Our overarching hypothesis is that the nexus between the SSH1 and Nrf2
pathways represents a tipping point that tips the balance between degeneration and protection
during proteotoxic and oxidative stress in tauopathies. As both Nrf2 and SSH1 are activated under
oxidative stress, understanding how the nexus between Nrf2 and SSH1 is physiologically and
pathologically regulated will provide key insights into treating AD and other tauopathies.
Utilizing in vitro recombinant proteins, cellular models, animal models, and postmortem brains
combined with mechanistic biochemical, immunochemical, in situ proximity ligation assays, RNA-
seq, and proteomics studies, we will define and dissect how the SSH1-Nrf2 nexus tips the balance
between neurodegeneration vs. neuroprotection in tauopathies.
Terms: <AD dementia><AD pathology><APP-PS1><APP/PS1><Actin Filaments><Actins><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amyloid><Amyloid Substance><Animal Model><Animal Models and Related Studies><Assay><Astrocytes><Astrocytus><Astroglia><Autophagocytosis><Autopsy><Binding><Binding Sites><Bioassay><Biochemical><Biological Assay><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Fractionation><Cell Nucleus><Cell Signaling><Cell model><Cells><Cellular Matrix><Cellular model><Closure by Ligation><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Combining Site><Cytoskeletal System><Cytoskeleton><Defect><Dephosphorylation><Deposit><Deposition><Disturbance in cognition><E3 Ligase><E3 Ubiquitin Ligase><Encephalon><Equilibrium><Exhibits><Expression Signature><F-Actin><FTLD><Filamentous Actin><Frontotemporal Lobar Degenerations><Frontotemporal variety lobar degeneration><Gene Expression><Gene Expression Profile><Gene Transcription><GeneHomolog><Genes><Genetic Transcription><Homolog><Homologous Gene><Homologue><Human><Impaired cognition><In Situ><In Vitro><Induction of Apoptosis><Intracellular Communication and Signaling><Knowledge><Lentivirinae><Lentivirus><Ligation><MT-bound tau><Mediating><Mice><Mice Mammals><Microfilaments><Mitochondria><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myofilaments><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neurons><Nuclear><Nucleus><Outcome><Oxidative Stress><Pathogenesis><Pathologic><Pathology><Pathway interactions><Phenotype><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Physiologic><Physiological><Primary Senile Degenerative Dementia><Protein Dephosphorylation><Protein Phosphorylation><Proteins><Proteome><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Recombinant Proteins><Regulation><Repression><Rod><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Synapses><Synaptic><Tauopathies><Testing><Titrations><Transcription><Transfection><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><abnormally aggregated tau protein><aging process><astrocytic glia><autophagy><balance><balance function><biological signal transduction><brain control><cofilin><cognitive defects><cognitive dysfunction><cognitive loss><cohort><filamentous tau inclusion><gene expression pattern><gene expression signature><global gene expression><global transcription profile><immunoreactivity><insight><intracellular skeleton><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mitochondrial><model of animal><mutant><necropsy><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuropathologic tau><neuropathological tau><neuroprotection><neuroprotective><oxidation><oxidative damage><oxidative injury><paired helical filament of tau><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><postmortem><primary degenerative dementia><proteotoxic><proteotoxicity><response><self-aggregate tau><senile dementia of the Alzheimer type><sensor><shRNA><short hairpin RNA><small hairpin RNA><subcellular fractionation><synapse><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 polymerization><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><ubiquitin-protein ligase><τ Proteins><τ aggregation>