# Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease

> **NIH NIH UG3** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $225,900

## Abstract

Abstract
Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost. While
genetic studies are increasingly identifying polymorphisms that correlate with AD, there still is no clear picture
of the molecular and cellular players and the extent to which each contributes to AD. The genetic and
molecular complexity of AD and the lack of technology for experimentally unraveling it in human tissues create
a bottleneck constricting the discovery of therapeutics and their successful translation into the clinic. Using
human iPSCs we recently developed an in vitro blood-brain barrier (iBBB) and deployed it to discover
mechanisms causing genetic predisposition to cerebral amyloid angiopathy (CAA). Identical to clinical studies,
we found that APOE4, the strongest genetic risk factor for CAA and AD significantly increased amyloid
deposition in our iBBB. The tractability of our engineered tissues then enabled dissection of the cellular causes
of the disease. We found expression of APOE4 in pericytes alone was sufficient to increase cerebral vascular
amyloid accumulation. Pinpointing the causal cells mediating CAA risk then enabled molecular and
biochemical studies that established the underlying mechanism and revealed new therapeutic opportunities for
mitigating genetic risk of CAA and potentially AD. Here, we will build upon our success, using the iBBB as a
scaffold; we will incorporate neurons, oligodendrocytes, and microglia to generate a micro-integrated brain on
a chip (miBrain-chip). In UG3 Aim1.1 we will establish miBrain-chips that represent healthy and diseased
states of the human brain through iterative rounds of optimization that incorporate state-of-the-art biopolymers
and engineering expertise from Robert Langer's lab at MIT. UG3 Aim1.2 will integrate and validate genetically
encoded modulators and reporters of neuronal activity enabling the miBrain-chip to investigate how neuronal
activity is influenced, and in turn, influences AD pathogenesis. UG3 Aim2 will model the pathological
progression of AD in miBrain-chips across cohort of male and female sAD iPSC lines for which we have
matched brains samples, clinical history, and genomic sequences. We will build computational models
describing the transcriptional, cellular-dynamics and histological transformations that lead up to the end-states
of post-mortem AD brains. These longitudinal pathological maps from genetically diverse healthy and sAD
individuals will yield mechanistic insight into AD development and create a platform for discovery and efficacy
screening of therapeutics. We hypothesize that the mechanisms underlying AD are significantly influenced by
genetic variability. In UH3 we will establish the mechanisms underlying APOE4 pathogenesis (UH3 Aim1) and
then ascertain the efficacy, toxicity, and therapeutic window of a panel of preclinical and clinical AD drugs
using isogenic APOE3 and APOE4 miBrain-chips (UH3 Aim2). Our multimodal strategy will sh...

## Key facts

- **NIH application ID:** 10241763
- **Project number:** 3UG3NS115064-01S1
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Joel William Blanchard
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,900
- **Award type:** 3
- **Project period:** 2019-09-20 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241763

## Citation

> US National Institutes of Health, RePORTER application 10241763, Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease (3UG3NS115064-01S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241763. Licensed CC0.

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