# Project 3 - Animal Models Examining Neurovasculature

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $874,035

## Abstract

PROJECT 3 – PROJECT SUMMARY/ ABSTRACT
Dysfunctionin the blood-brain barrier (BBB) and each of the cellular components of the neurovascular unit (NVU)
– vascular cells, glial cells, and neurons – has been linked to Alzheimer’s disease (AD) evolution in experimental,
imaging, pathological, and epidemiological studies. These findings have led to an emerging ‘neurovascular
hypothesis’ of AD which holds that cerebrovascular dysfunction contributes to cognitive decline and dementia
in AD. Project 3 supports the overall theme of P01 focused on apolipoprotein E (APOE) gene, the major genetic
risk factor for AD, by interrogating the BBB/neurovascular hypothesis experimentally at the cellular, molecular
and systems levels and in an isoform-specific and gender-specific fashion using novel APOE3 and APOE4knock
in (KI)flox/flox mice (E3F; E4F) with and without apoE deletion from astrocytes and pericytes (the key sources of
BBB-associated apoE), and with and without Aβ and tau pathology. Based on our pilot and published data we
hypothesize that 1) Disrupted blood-brain barrier (BBB) protein-protein interaction (PPI) signaling networks
underlying endothelial barrier disruption and BBB dysfunction will precede and predict synaptic and neuronal
dysfunction and behavioral changes driven by APOE4 relative to APOE3 in new APOE KIF lines both without
and with AD pathology; and 2) 3K3A-activated protein C (APC), a cell signaling analog of APC, will correct
dysregulated BBB and PSD95 synaptic PPI signaling networks, will protect BBB and neuronal function, and
diminish AD pathology, thereby delaying onset and slowing down disease progression in APOE/AD models. To
test our hypothesis, we will use novel E3F and E4F mice alone and crossed i) with Cre lines that specifically
express Cre recombinase in astrocytes and pericytes to determine the effects of cell-specific deletion of the key
BBB-associated apoE source(s) and ii) with APP/PS1-21 mice and P301S tau mice to investigate interactions
with Aβ and tau pathways. To evaluate BBB/vascular dysfunction we will use: 1) advanced molecular
assessment of the BBB by simultaneously measured BBB/NVU cell-specific and Aβ and tau biomarkers in CSF
and plasma; 2) a novel BBB proteomics analysis; 3) advanced MRI assessment of BBB and CBF; and 4)
validation of biofluid biomarkers by tissue analysis. To evaluate synaptic and neuronal dysfunction we will
use: 5) PSD95 interactomeanalysis; and 6) viral tract-tracing of hippocampal pathways in the Papez circuit/DMN;
and 6) behavior and 7) neuropathology analysis. We will evaluate apoE-allele-specific effects on BBB and
neuronal dysfunction by biofluid, tissue and imaging biomarkers, BBB and PSD95 PPI analysis, hippocampal
viral tract-tracing, and behavior in APOE KIF mice(male, female) at different ages with and without apoE deletion
from astrocytes and pericytes (AIM 1), crossed with APP/PS1-21 and P301S tau micein relation to AD pathology
(AIM 2), and will evaluate 3K3A-APC therapy in AP...

## Key facts

- **NIH application ID:** 10621719
- **Project number:** 5P01AG052350-07
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Marcelo Pablo Coba
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $874,035
- **Award type:** 5
- **Project period:** 2016-09-30 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621719

## Citation

> US National Institutes of Health, RePORTER application 10621719, Project 3 - Animal Models Examining Neurovasculature (5P01AG052350-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10621719. Licensed CC0.

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