# A high-throughput, quantitative platform using 2D dissociated human cerebral organoids to model neuroinflammation in Alzheimer’s disease

## TL;DR

Researchers developed a high-throughput platform using human brain organoids infected with HSV-1 to model Alzheimer’s disease-related neuroinflammation and test potential therapies.

## Contribution

A novel high-throughput framework using 2D dissociated cerebral organoids infected with HSV-1 to model AD-related neuroinflammation and screen therapeutics.

## Key findings

- HSV-1 infection in dissociated cerebral organoids leads to co-abundance of beta amyloid and phosphorylated tau, resembling AD pathology.
- Secreted Aβ42/40 ratios were lower in HSV-1-infected organoids compared to controls.
- HSV-1-infected organoids showed enriched AD-associated gene expression patterns from RNA sequencing.

## Abstract

Neuroinflammation is a key process associated with Alzheimer’s disease (AD). There is interest in developing New Approach Methodologies (NAMs) by using human in-vitro complex systems such as brain organoids, combined with machine learning and computational approaches, to reproducibly and robustly evaluate monoclonal antibodies and other therapeutic modalities on these human-derived systems. Herpesviruses such as herpes simplex virus 1 (HSV-1) had been shown to be associated with AD risk and molecular pathology. Building on top of previously reported work, we used herpes simplex virus 1 (HSV-1) infection in 2D dissociated cells from human cerebral organoids (dcOrgs) to recapitulate AD-associated molecular readouts, such as high co-abundance of intracellular beta amyloid (Aβ) and phosphorylated tau (pTau) with HSV-1. Secreted Aβ42/40 ratios in conditioned media were lower from HSV-1-infected dcOrgs, compared to mock dcOrgs. Differentially expressed transcripts from bulk and single-cell RNA sequence data in HSV-1-infected dcOrgs were enriched for AD-associated GWAS genes. Our high-throughput, quantitative framework represents a comprehensive approach to harness on the strengths of 2D dcOrgs for high-throughput applications such as therapeutic screens and can complement the 3D brain organoids and animal models for neuroinflammation in AD.