Summary Project
Clinical and preclinical studies have demonstrated perturbations to the cerebrovascular network in
Alzheimer’s Disease (AD) in sex-specific manner. Altered blood flow, cerebrovascular reactivity, and vessel
topologies are all hallmarks of progressing AD in animal models and in human subjects. Blood-borne protein
biomarkers have reported altered profiles in humans and mouse models of AD. AD research has
predominately focused on neuronal, inflammatory and glial markers of disease progression. At the present
time there are no studies that directly relate AD-induced changes in angioarchitecture to blood-borne protein
biomarkers of endothelial stress and vascular dysfunction. Similarly, there are no studies linking blood borne
protein biomarkers to vessel genomics, specifically targeting endothelial cell genes. This is a critical gap with
significant clinical value because several studies suggest that vascular abnormalities precede AD onset.
Therefore, blood-borne protein biomarkers could be used to predict likelihood of vulnerability to AD, disease
onset and progression. This gap in knowledge will be addressed by this proposal, with the goal of describing
the temporal evolution and relationships between damaged vascular networks and blood-based protein
biomarkers and vascular genes. We have previously reported in AD mouse models there is an altered
vascular density and complexity with increasing age. Sex differences have also been poorly studied within
the context of vascular biomarkers, a gap we will also directly address in this proposal. Four interrelated but
not interdependent Aims will elucidate the relationship between vessel genomics, cerebrovascular structure
and function modifications and blood-borne protein biomarkers of endothelial and vascular functions. Aim 1
will examine in fine detail the timeline of vascular function structural changes over the lifetime (4, 12, >18mo)
in 5xFAD mice of both sexes. Known risk variants will be added to clarify the effects of amyloid β seeding.
The blood-based biomarkers will focus on proteins of endothelial stress, vascular damage and recovery
(VEGF, vWF, Claudin-5, etc), glial (GFAP), inflammation (IL-1b, TNFa, HMGB1, IL6, MMP9) and neuronal
damage and neurodegeneration (NF-L, Tau and its various phosphorylated forms and Abeta40 and 42). We
believe that a panel of blood-borne biomarkers will accurately reflect the underlying cerebrovascular
abnormalities with increasing age. Aim 2 will utilize the 3xTg AD mouse that has early amyloid β followed by
tau deposition and 3xTg mice with the addition of risk variants. Aims 1-3 will utilize the identical methods
biomarkers, genomes and structure/function assessments. Aim 4 will model all the findings to identify a
unique biomarker set that has predictive capabilities for AD onset. The proposed project will provide technical
and conceptual innovations through using a unique combinatory approach to establish direct relationships
between blood-borne biomarkers and vascular function and topology, as well as genomic markers from the
same animals of both sexes using PWI MRI, 2-photon microscopy, vessel painting, state-of-the-art spatial
transcriptomics and single-nucleus RNA-seq and blood-borne protein biomarkers. Such innovative
biomarkers would enable early identification of patients with elevated risk for AD, prediction of AD onset and
severity, and objective monitoring treatment efficacy, our long-term research objectives.
