# Big data and small molecules for Alzheimer's disease

> **NIH NIH RF1** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $412,500

## Abstract

Abstract
 The goal of this administrative supplement application is to use our high resolution metallomic imaging
mass spectrometry (hr-MIMS) for brain mapping of microvascular impairment associated with the pathogenesis
and progression of Alzheimer's disease (AD). Specifically, we propose to perform phenotype analyses conducted
under our NIA-funded RF1 project (“Big Data and Small Molecules for Alzheimer's Disease” 1RF1AG063913-
01) by applying innovative, state-of-the-art mass spectrometry techniques to characterize brain phenotypic
endpoints. The funded RF1 parent project is designed to identify specific ACEI+STAT medications in a large
national database and test the efficacy of ACEI+STAT combination therapy to suppress pathological phenotypes
in tauopathy mouse models. In this supplement proposal, we will add phenotype analysis in the same mouse
model. We will investigate brain microvascular impairment and corresponding imaging and biomarkers linked to
tauopathy pathogenesis and progression. The rationale for broadening project scope is supported by: (i) clinical
evidence linking vascular pathologies with AD; (ii) new findings from the collaborating PIs (and others) that point
to microvasculopathy and blood-brain barrier (BBB) dysfunction as key drivers of tau protein pathology and
progression, (iii) recent acquisition of state-of-the-art mouse neuroimaging and mass spectrometry resources
that enable translation of clinically-relevant brain imaging for eventual use in humans. The new aim leverages
the same well-characterized tauopathy mouse models (P301L mice expressing mutant human tau) included in
the funded parent project. This model exhibits progressive microvasculopathy, tauopathy, and
neurodegeneration relevant to AD pathogenesis and progression. We will systematically investigate the temporal
and spatial patterning of brain pathologies with added focus on microvascular dysfunction and relationship to
corresponding neuroimaging. We plan to achieve one Aim to test our hypothesis that tauopathy,
microvasculopathy and neuronal loss can be tracked by metallomic imaging and staining of biomarkers of brain
vascular health. We aim to investigate temporal, anatomical, and mechanistic linkage among tauopathy and
microvasculopathy in a genetic AD mouse model expressing mutant human P301L tau. Sub-Aim 1A: Evaluate
brain microvasculopathy by molecular marker profiling (SAA, CRP, VCAM-1, ICAM-1) and high-resolution
metallomic imaging mass spectrometry (hr-MIMS) brain mapping in a tauopathy model as a function of age and
disease progression. Sub-Aim 1B: Correlate results from Sub-Aim 1A with quantitative immunohistochemical
analysis of harvested brains targeting key pathological endpoints (phosphorylated tauopathy, p-tau/tau;
neuroinflammation, Iba-1; astrocytosis, GFAP; neuronal loss) relevant to progression of tauopathy. We will test
whether microvascular-BBB dysfunction will anatomically colocalize and mechanistically link with progression of
tauo...

## Key facts

- **NIH application ID:** 10217833
- **Project number:** 3RF1AG063913-01S2
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** LEE E. GOLDSTEIN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,500
- **Award type:** 3
- **Project period:** 2019-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217833

## Citation

> US National Institutes of Health, RePORTER application 10217833, Big data and small molecules for Alzheimer's disease (3RF1AG063913-01S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217833. Licensed CC0.

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