# Dysfunctional Endosomal-Mediated Mitochondrial Clearance Linking Vascular Dysfunction to Alzheimer's Disease: Administrative Supplement for HL148756

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $355,381

## Abstract

PROJECT SUMMARY
This application is being submitted in response to NOT-AG-21-018. Alzheimer's disease (AD) is a progressive
neurodegenerative brain disease and the most common type of dementia affecting nearly 47 million people
worldwide. AD cases (∼98 %) are prevalent in aging subjects and often involve various other co-morbidities
including obesity and diabetes. Accumulating evidence shows that diabetes is an independent risk factor of AD.
Obesity and diabetes are known to cause damage to vascular cells including endothelial cells and pericytes, and
various studies have demonstrated that cellular homeostasis of these cells are essential for the integrity of the
blood-brain-barrier (BBB), the disruption of which has been observed in many CNS pathologies, including AD
and vascular dementia. However, due to the relative inaccessibility of functional human brain tissues for research,
the underlying mechanisms of diabetes-induced cognitive impairment linked to vascular damage remain poorly
understood. To that end, in this Alzheimer’s-focused administrative supplement, we aim to use diabetic patient-
specific induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) and iPSC-
derived pericytes in 2D and 3D cultures to model this diseased phenotype in a dish. In Aim 1, we will generate
iPSC-BMECs and iPSC-pericytes from healthy and diabetic patients, and test whether a novel RAB5/7-
dependent endosomal-mediated mitochondrial degradation pathway is disrupted in these cells during
hyperglycemia. We will functionally characterize how impairment of this degradation pathway in the presence of
hyperglycemia will affect the phenotype of iPSC-BMECs and iPSC-pericytes. This is based on our parent grant
R01 showing that this pathway was affected in cardiomyocytes who are at heightened risk against diabetes. In
Aim 2, we will use a novel Brain-Chip platform to generate an in vitro 3D blood-brain barrier-like structure (the
neurovascular unit) comprising of isogenic CRISPR RAB7 KO iPSC-BMECs and iPSC-pericytes, along with
isogenic healthy iPSC-astrocytes, and iPSC-neurons as a more physiological relevant platform to investigate the
effects of cell-cell interaction on hyperglycemia/RAB7-KO induced BBB integrity disruption. Single cell RNA
sequencing to identify cross-talk between dysfunctional vascular cells and neurons and glial cells will also be
performed. Overall, the platform we will be establishing can serve as a proof-of-principle to test druggable targets
that can ameliorate cognitive deficits or various types of neurodegenerative diseases caused by diabetes.

## Key facts

- **NIH application ID:** 10498355
- **Project number:** 3R01HL148756-03S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Sang Ging Ong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $355,381
- **Award type:** 3
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498355

## Citation

> US National Institutes of Health, RePORTER application 10498355, Dysfunctional Endosomal-Mediated Mitochondrial Clearance Linking Vascular Dysfunction to Alzheimer's Disease: Administrative Supplement for HL148756 (3R01HL148756-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10498355. Licensed CC0.

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