This $1,823,353 Project Grant awarded by the National Institute on Aging (CFDA 93.866 Aging Research) to the Seattle Institute For Biomedical And Clinical Research aims to elucidate the molecular mechanisms by which pathological tau protein causes neurodegeneration in Alzheimer's disease (AD) and related tauopathy disorders. The research project will leverage a C. elegans model of tauopathy to investigate the functional role of nuclear speckles, membraneless organelles involved in RNA...
This Project Grant award from the National Institute on Aging (CFDA 93.866 Aging Research) provides $1,592,854 to the University of Illinois to conduct research on tau protein conformation and its role in Alzheimer's disease and related dementias. The key focus areas include: Defining the effects of tau post-translational modifications on tau function and pathology. This will evaluate how modifications like phosphorylation, acetylation, and cross-linking impact the exposure of tau's regulatory...
This federal Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) will support research at Virginia Commonwealth University (VCU) to investigate the effect of the trans-synaptic spread of pathogenic tau protein in the hippocampus and its impact on vulnerable neuron subtypes in Alzheimer's disease (AD). The $408,638 award, effective from August 1, 2024 to July 31, 2026, will involve the use of adeno-associated viral vector transfection, immunofluorescence, and...
This Project Grant award from the National Institutes of Health's Aging Research program (CFDA 93.866) will support research to identify early transcriptional and pathological changes in brain regions vulnerable to Alzheimer's disease (AD). The $459,076 award, granted to Trustees of Boston University, will use single-nucleus RNA sequencing and targeted mass spectrometry to profile cell type-specific gene expression and tau/amyloid beta proteoforms in the transentorhinal cortex, entorhinal...
This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $717,709 to Weill Medical College of Cornell University to conduct research on the mechanisms underlying the propagation of tau aggregates in Alzheimer's disease (AD) and frontotemporal dementia (FTD). The research aims to discover AD-relevant cellular machinery involved in the spread of misfolded tau proteins using advanced proteomic and transcriptomic techniques. The work will be carried out...
This Project Grant award from the National Institute on Aging (CFDA 93.866 Aging Research) provides $784,596 to Northeastern University to conduct comprehensive and cell type-specific proteogenomic profiling of aberrant and mis-processed proteins in Alzheimer's disease (AD) and tauopathy models. The project aims to substantially expand understanding of protein dysfunctions in AD by applying state-of-the-art proteomic methods paired with proteogenomics across multiple brain regions, AD stages,...
This Project Grant award of $773,816, provided by the National Institute on Aging (CFDA 93.866 - Aging Research), aims to conduct cell-type-specific and spatial proteogenomics analysis of aberrant RNA splicing and misfolded proteins in Alzheimer's-related tauopathies. The research team from the University of California, Irvine will comparatively study new tau-directed Alzheimer's disease mouse models and human Alzheimer's brain tissues to generate single-cell spatial proteo-transcriptomics...
This Project Grant award of $816,661 from the National Institute on Aging (CFDA 93.866 - Aging Research) will support a comprehensive research project entitled "Aberrant Proteomes in Tauopathy: Revealing Functional Consequences via Multimodal Proteomics". The research, conducted by The Regents of the University of California, San Francisco, aims to systematically elucidate the molecular and cellular mechanisms by which pathological tau drives neurodegeneration in Alzheimer's disease...
This $2,190,943 federal Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) supports a research study conducted by the University of Alabama at Birmingham (UAB) to examine the relationship between tau protein deposition and functional brain network health in individuals at risk for Alzheimer's disease (AD). The key objectives of the study are to: 1) Use tau positron emission tomography (PET) and resting-state functional magnetic resonance imaging (fMRI) to...
This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) to The General Hospital Corporation, doing business as Massachusetts General Hospital (MGH), provides $487,574 in funding to investigate the role of reactive astrocytes in the propagation and clearance of tau protein in Alzheimer's disease. The key objectives are to: Determine if astrocyte GFAP (glial fibrillary acidic protein) upregulation can attenuate the trans-synaptic neuron-to-neuron propagation of...
SELECTIVE VULNERABILITY AND RESILIENCE TO TRANS-SYNAPTIC PATHOLOGICAL TAU SPREADING IN ALZHEIMERS DISEASE - PROJECT SUMMARY THE INCIDENCE OF ALZHEIMER'S DISEASE (AD) IS ON THE RISE, AND WE ARE IN DIRE NEED OF EFFECTIVE TREATMENTS. IN AD, THE SPATIOTEMPORAL PROGRESSION OF TAU PATHOLOGY WITHIN THE CNS REMAINS THE STRONGEST NEUROPATHOLOGICAL CORRELATE OF COGNITIVE IMPAIRMENT, THUS CONSTITUTING A LIKELY EFFECTIVE TREATMENT TARGET ( LONG- TERM GOAL). COMPELLING EVIDENCE SUPPORTS A TRANS-SYNAPTIC FRAMEWORK FOR PATHOLOGICAL TAU SPREADING, DRIVEN PRIMARILY BY THE PROPAGATION OF TOXIC SOLUBLE TAU OLIGOMER (TAUO) CONFORMERS BETWEEN FUNCTIONALLY CONNECTED BRAIN REGIONS. NUMEROUS INVESTIGATIONS FURTHER POSTULATE THE INFLUENCE OF AMYLOID-BETA (AB) ON TRANS- NEURONAL PATHOLOGICAL TAU SPREADING, WHILE EMERGING EVALUATIONS OF PRIMARY TAUOPATHIES (E.G. PRIMARY AGE RELATED TAUOPATHY-PART), WHICH LACK AB, OBSERVE LIMITED REGIONAL TAU SPREADING ALONGSIDE LITTLE-TO-NO AMNESTIC CHANGES. WITHIN THE TRANS-SYNAPTIC SPREADING FRAMEWORK, HOWEVER, THE PRECISE MECHANISMS BY WHICH TAUO SELECTIVELY ENGAGE KEY SYNAPTIC SUBTYPES (E.G. EXCITATORY VS. INHIBITORY), AND THE ROLE OF AB IN THIS PROCESS, REMAIN UNKNOWN. WE THUS HYPOTHESIZE THAT AB MODULATES PATHOLOGICAL TAU SPREADING BY INCREASING OLIGOMERIC TAU BINDING AND INTERNALIZATION TO VULNERABLE SYNAPSES. TO SUPPORT THIS HYPOTHESIS, WE PROVIDE NOVEL PRELIMINARY EVIDENCE FOR INCREASED BINDING AND INTERNALIZATION OF TOXIC TAUO BINDING IN THE PRESENCE OF SOLUBLE AB OLIGOMERS IN HUMAN SYNAPSES. IN AIM 1, WE WILL DETERMINE THE ROLE OF ABO IN MODULATING SYNAPTIC TAUO BINDING WITHIN A FRAMEWORK OF CELLULAR, REGIONAL AND CLINICAL RESILIENCE TO PATHOLOGICAL TAU BURDEN. IN AIM 2, WE WILL DETERMINE KEY SYNAPTIC PROTEINS THAT MODULATE THE BINDING AND/OR INTERNALIZATION OF TAUO IN THE PRESENCE AND ABSENCE OF ABO. TO EXECUTE THESE AIMS, WE HAVE DEVELOPED AN INNOVATIVE AND TRANSLATIONALLY RELEVANT APPROACH TO INTERROGATE MECHANISMS OF TAU BINDING DIRECTLY IN HUMAN SYNAPSES ISOLATED FROM POST-MORTEM AUTOPSY SPECIMEN USING AN ARRAY OF BIOCHEMICAL TECHNIQUES. AT THE COMPLETION OF THIS PROJECT, WE EXPECT TO DOCUMENT PREVIOUSLY UNAPPRECIATED MECHANISMS THAT MODULATE SYNAPTIC TAUO BINDING AND INTERNALIZATION-A KEY COMPONENT OF PATHOLOGICAL TAU SPREADING.