# Molecular and Cellular Pathways Regulating Neurovascular Dysfunction in Degenerative Tauopathies

> **NIH NIH R56** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $827,748

## Abstract

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...

## Key facts

- **NIH application ID:** 10236690
- **Project number:** 1R56AG069115-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** LEE E. GOLDSTEIN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $827,748
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236690

## Citation

> US National Institutes of Health, RePORTER application 10236690, Molecular and Cellular Pathways Regulating Neurovascular Dysfunction in Degenerative Tauopathies (1R56AG069115-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10236690. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*