The cardinal pathological features of Alzheimer’s disease (AD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), and other tau protein AD-related dementias (ADRDs) are commonly accompanied by microvascular abnormalities. Clinicopathological findings in human brains and experimental animal studies suggest that microvascular dysfunction and blood-brain barrier (BBB) disruption modulate the location, severity, and progression of neuroinflammation, tauopathy, and neurodegeneration in these diseases. The goal of this proposal is to identify and characterize the complexity of molecular and cellular pathways underpinning microvascular-BBB dysfunction associated with tau protein neurodegenerative diseases. This multi-PI project will use synergistic tools and expertise to comprehensively identify the mechanisms that drive neurovascular modulation of tau-mediated neurodegeneration. We hypothesize that conserved molecular pathways associated with BBB dysfunction are differentially expressed in the critical cell types of the neurovascular unit (endothelia, pericytes, astrocytes, neurons) and drive neurodegeneration in genetic and trauma-induced tauopathies relevant to AD and CTE. Here we propose a rigorous systematic investigation that utilizes well-characterized mouse models of tauopathy to elucidate common molecular and cellular determinants that drive microvascular dysfunction, progressive neurodegeneration, and cognitive decline. We will combine these models with a novel toolkit for cell-specific deep transcriptional profiling to comprehensively identify cell type-specific molecular pathways and temporal patterning of gene expression profiles associated with NVU dysfunction and tau proteinopathy. Microvascular-BBB functional integrity will be evaluated using advanced in vivo neuroimaging (DCE-MRI), ex vivo Gd-metallomic imaging mass spectrometry brain mapping (Gd-MIMS), and ultrastructural and molecular pathology as a function of tauopathy progression in: (i) PS19 (P301S) transgenic mouse model of genetic tauopathy (SA1), and (ii) a novel repetitive head injury mouse model of progressive tauopathy and neurodegeneration (SA2). We will use regression modeling to determine the relationship between cell type-specific transcriptional programs, BBB dysfunction, and tau accumulation as a function of neurodegenerative insult (genetic vs traumatic), age, and sex. In SA3 (Sub-Aim 3A), we will analyze combined datasets from SA1 and SA2 to ascertain conserved and distinct functional molecular pathways in the dynamically interacting cell types within the NVU across the model tauopathies. In SA3 (Sub-Aim 3B), we will validate the relevance of identified cell-specific NVU molecular pathways from SA1 and SA2 in relevant human brain specimens from the NIH/NIA-funded Boston University Alzheimer’s Disease and CTE Center Brain Bank and blood samples from the NIH/NINDS-funded MarkVCID Consortium. With unique tools and complementary expertise, we are poi...