# Cell and Molecular Consequences of Alzheimer's Disease Genetic Variants on BBB Integrity and Function

> **NIH NIH RF1** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $3,598,522

## Abstract

Blood-brain barrier (BBB) dysfunction has been shown to play a causal role in both early- and late-onset
Alzheimer's disease (EOAD, LOAD). While much has been learned about the molecular mechanisms of BBB
function and dysfunction in AD from mouse model systems, many important unanswered questions remain
regarding how AD-associated mutations and genetic variants affect human BBB integrity and function.
Improved human experimental systems are required to complement existing animal models. Pioneering
studies by co-PI Ingber have produced microfluidic 3D organ-on-chip models, including a BBB-on-a-chip (BBB-
Chip), increasingly representative of human in vivo physiology. We have adapted this system to create
isogenic iPSC-derived BBB-Chip models of normal human subjects and of subjects with EOAD and LOAD.
The Young-Pearse lab has generated a collection of iPSC lines that capture the diverse set of genetic risk
factors for AD including: EOAD mutation of APP and corrected controls, DS and DS with removal of copies of
high impact chr21 genes, an isogenic APOE series including APOE 2/2, 3/3, 4/4 and KO, and a collection of
lines that we've generated from over 50 individuals in the ROS/MAP cohorts that represent the clinical and
pathological spectrum of LOAD. Here, we propose to combine the BBB-Chip model with the iPSC line
collection to examine the impact of early- and late-onset genetic variants on BBB function, and to define the
molecular pathways impacted by these variants. In the first aim, we address the hypothesis that neurons
expressing EOAD mutations secrete Aβ species that negatively affect BBB integrity through toxic effects on
brain microvasculature endothelial cells (BMVECs). We will use human BBB in vitro models to examine Aβ-
dependent and independent impacts of trisomy 21 and fAD mutation on BBB integrity and function via a)
measurements of transendothelial electrical resistance (TEER), b) permeability assays, and c)
immunocytochemistry and morphological analyses of BBB cells. In addition, we will identify the molecular
pathways affected in EOAD in BMVECs, pericytes and astrocytes via RNA sequencing and unbiased
proteomics. In aim 2, we determine the functional impact of altered composition of Aβ aggregates on clearance
of pathologic Aβ across the BBB. To this end, we will use a variety of well defined synthetic Aβ species as well
as human neuron-derived and brain-derived Aβ to systematically define how Aβ composition and aggregation
state affects: 1) uptake and transcytosis of Aβ across the BBB and 2) integrity of the BBB and health of the
pericytes, astrocytes and BMVECs composing the BBB. Finally, in the third aim we address the hypothesis that
the LOAD risk genes SORL1 and CLU work in concert with APOE to mediate Aβ clearance by the BBB. In this
aim, we will determine the functional consequences of variants of APOE, CLU and SORL1 on BBB integrity
and Aβ clearance. Finally, we will determine the molecular consequences of modulation of AP...

## Key facts

- **NIH application ID:** 10037760
- **Project number:** 1RF1NS117446-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Tracy L YOUNG-PEARSE
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,598,522
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10037760

## Citation

> US National Institutes of Health, RePORTER application 10037760, Cell and Molecular Consequences of Alzheimer's Disease Genetic Variants on BBB Integrity and Function (1RF1NS117446-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10037760. Licensed CC0.

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