Big data and small molecules for Alzheimer's disease

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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 tauopathy in the mouse model.