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Principal Investigator: Jennifer Nicole Rauch
Organization: UNIVERSITY OF MASSACHUSETTS AMHERST
Fiscal Year: 2024
Award: $87,281
Funding agency: National Institute on Aging
Several neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by the spread and
aggregation of the protein tau. Recently, we identified a cellular receptor, LRP1 (Low-density lipoprotein
Receptor-related Protein 1), that regulates the tau spread pathway. Knockdown of LRP1 prevents tau spread
in human iPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important
entry point for disease intervention. Unfortunately, a detailed understanding of the tau-LRP1 molecular complex
is still lacking. Therefore, the main objective of this project is to define the tau-LRP1 structural interface and
discern how post-translation modifications (PTMs) to tau’s structure influence tau uptake and spread. In
preliminary work, we have developed protocols to purify and measure interactions between tau and LRP1. We
have established cellular platforms to model tau propagation and have shown that this process can be influenced
by tau PTMs. To fully develop this work, we propose three aims. In Aim 1, we will use TR-FRET to establish in
vitro affinities between tau and LRP1 and mass spectrometry to map the protein-protein interface. In Aim 2, we
will look at how tau phosphorylation can influence the tau-LRP1 complex and what effect this has on tau spread
and aggregation. In Aim 3, we will focus on tau PTMs that alter lysine residues. We will assess if ubiquitination
or acetylation can impact the tau-LRP1 interaction, if they influence tau aggregation, and if they promote or inhibit
tau uptake and seeding in cells. The innovative experimental methods and comprehensive analyses outlined
herein will provide important mechanistic insight and develop our understanding of pathogenic tau regulation in
AD. This will be an essential first step forward for the development and evaluation of potential AD therapeutics.
Terms: <3-D><3-Dimensional><3D><AD dementia><AD pathology><APF-1><ATP-Dependent Proteolysis Factor 1><Acetylation><Affinity><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><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 therapeutic><Alzheimer's disease therapy><Alzheimer's pathology><Alzheimer's therapeutic><Alzheimer's therapy><Alzheimers Dementia><Amber><Apo E Receptor><ApoE Receptor><Apolipoprotein E Receptor><Assay><Bioassay><Biochemical><Biological><Biological Assay><Brain><Brain Nervous System><Cell Body><Cell Culture Techniques><Cells><Charge><Codon><Codon Nucleotides><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Degenerative Neurologic Disorders><Deposit><Deposition><Development><Disease><Disease Progression><Disorder><Dissection><Electron Cryomicroscopy><Electrostatics><Elements><Encephalon><Evaluation><FRET><Fluorescence Resonance Energy Transfer><Förster Resonance Energy Transfer><Genetic><Goals><HMG-20><High Mobility Protein 20><Human><In Vitro><Induced pluripotent stem cell derived neurons><Intervention><Intervention Strategies><Isoforms><Knowledge><L-Lysine><LDL-Receptor Related Protein 1><Learning><Ligands><Link><Lipoprotein Receptor><Low Density Lipoprotein Receptor-Related Protein><Low-Density-Lipoprotein Receptor-Related Protein-1><Lysine><MT-bound tau><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Methods><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Murine><Mus><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron from iPSC><Neuron from induced pluripotent stem cells><Pathogenicity><Pathologic><Pathway interactions><Phosphorylation><Point Mutation><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Senile Degenerative Dementia><Process><Protein Isoforms><Protein Modification><Protein Phosphorylation><Proteins><Protocol><Protocols documentation><Publishing><Receptor Protein><Regulation><Sampling><Site><Structure><Surface><Tauopathies><Technology><Testing><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><Work><abnormal tau><abnormally aggregated tau protein><alpha-2-Macroglobulin Receptor><alpha2-Macroglobulin Signaling Receptor><biologic><cell culture><cell cultures><compare to control><comparison control><cryo-EM><cryoEM><cryogenic electron microscopy><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><density><developmental><effective therapy><effective treatment><filamentous tau inclusion><hiPSC><human disease><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS neurons><iPSC derived-neurons><in vivo><induced human pluripotent stem cells><induced pluripotent stem cell neurons><innovate><innovation><innovative><insight><insoluble aggregate><interventional strategy><knock-down><knockdown><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule associated protein tau mutation><microtubule bound tau><microtubule-associated protein tau mutation><microtubule-bound tau><mutant tau><mutation in microtubule associated protein tau><mutation in microtubule-associated protein tau><neurodegenerative illness><neurons derived from induced pluripotent stem cells><neuropathologic tau><neuropathological tau><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-natural amino acids><non-proteinogenic amino acids><nonproteinogenic amino acids><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><p-tau><p-τ><paired helical filament of tau><pathogenic tau><pathogenic tau gene mutation><pathological change in tau><pathway><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><prevent><preventing><primary degenerative dementia><protein aggregate><protein aggregation><protein protein interaction><receptor><self-aggregate tau><senile dementia of the Alzheimer type><tau><tau PHF><tau Proteins><tau abnormality><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau interaction><tau intronic mutation><tau mediated neurodegeneration><tau mutation><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau pathological change><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><therapeutic target><three dimensional><treatment strategy><ubiquination><ubiquitin conjugation><unnatural amino acids><unpublished works><uptake><τ Proteins><τ aggregation><τ interaction><τ mutation><τ phosphorylation>