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Principal Investigator: Judith A Steen
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $778,347
Funding agency: National Institute on Aging
Project Summary/Abstract
In Alzheimer's disease (AD), the accumulation of intracellular posttranslationally modified Tau aggregates, is a
hallmark of AD pathology and a strong correlate of cognitive impairment. While the dozen or so
Posttranslational Modifications (PTMs) on Tau in pathological aggregates have been studied for decades, our
new quantitative and qualitative mass spectrometry approaches have discovered ~100 PTMs in the angular
gyrus from 98 human Alzheimer's Disease patients in these aggregates, i.e. Braak stages V/VI, and age
matched control subjects without pathological changes in the frontal lobe. In this proposal, we aim to develop
a large-scale proteomics platform to map the temporal occurrence of PTMs as disease progresses. We will
examine a valuable new set of cases, selected to encompass all Braak stages from 0 to VI. All cases in this
new cohort will have detailed premortem clinical data, which will allow us to detect and assess correlations
between clinical and pathophysiological findings and any tau PTM that is identified in this study. For this
analysis, we will study 3 brain regions (entorhinal/amygdala, and temporal and visual cortex) in 20 Braak 0
subjects; 40 early stage Braak I/II subjects; 40 mid stage Braak III/IV subjects; and 40 end stage Braak V/VI
subjects. We will also map the global proteomes of the brain specimens from this well-characterized patient
cohort to identify the enzymes associated with these Braak stage dependent PTMs. The findings of the tau
characterization and mapping of the proteomes will be validated using widely accepted Tau sensor assays
used to study Tau aggregation in AD.
In summary, this Tau PTM specific dataset, the deep proteome maps and the subsequent validation
experiments in seeding assays will be used to test our overarching hypothesis: Understanding how the
progressive accumulation of Tau PTMs results in the toxicity and seeding competence of tau, and mapping the
disease progression dependence of these PTMs and the enzymes responsible for them will allow us to develop
interventional strategies at earlier and prodromal stages of disease.
Terms: <AD dementia><AD pathology><Active Follow-up><Affect><Age><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Assay><Autopsy><Bio-Informatics><Bioassay><Biochemistry><Bioinformatics><Biologic Models><Biological Assay><Biological Chemistry><Biological Models><Body Tissues><Brain><Brain Nervous System><Brain region><Cell Body><Cells><Clinical><Clinical Data><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Competence><Consensus Sequence><Data><Data Set><Dependence><Development><Disease><Disease Progression><Disorder><Disturbance in cognition><Encephalon><Enzyme Gene><Enzymes><Exhibits><Goals><Human><Impaired cognition><In Vitro><Inferior><Intervention><Intervention Strategies><Isoforms><Kinases><Learning><MT-bound tau><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Methodology><Methods><Model System><Modern Man><Modification><Molecular><Nature><Nerve Degeneration><Neurofibrillary Tangles><Neuron Degeneration><Pathologic><Pathology><Patients><Pattern><Phenotype><Phosphopeptides><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><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><Protein Isoforms><Protein Modification><Protein Phosphorylation><Proteins><Proteome><Proteomics><Research Specimen><Signal Pathway><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Site><Specimen><Temporal Lobe><Testing><Therapeutic><Tissue Sample><Tissues><Toxic effect><Toxicities><Transphosphorylases><Validation><Visual Cortex><Work><abnormally aggregated tau protein><active followup><ages><amygdaloid nuclear complex><angular gyrus><brain tissue><cognitive dysfunction><cognitive loss><cohort><developmental><enzyme activity><experiment><experimental research><experimental study><experiments><filamentous tau inclusion><follow up><follow-up><followed up><followup><frontal cortex><frontal lobe><human disease><human subject><human tissue><in vivo><interventional strategy><large data sets><large datasets><life span><lifespan><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><necropsy><neural degeneration><neurodegeneration><neurodegenerative><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurofibrillary tangle formation><neurological degeneration><neuronal degeneration><novel><p-tau><p-τ><paired helical filament of tau><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><phospho-proteomics><phospho-tau><phospho-τ><phosphoproteomics><phosphorylated tau><post-translational modification of tau><postmortem><posttranslational modification of tau><primary degenerative dementia><prion-like><self-aggregate tau><senile dementia of the Alzheimer type><sensor><tangle><tangle formation><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau factor><tau fibrillization><tau filament><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><temporal cortex><validations><visual cortical><τ Proteins><τ aggregation><τ phosphorylation>