# Preexisting Genetic Background Primes the Responses of Human Neurons to Amyloid β

## TL;DR

This study shows that amyloid beta's effects on human neurons depend on their genetic background, triggering inflammation and cell movement in some neurons.

## Contribution

The study reveals that Aβ-induced responses in human neurons are genetically modulated, with distinct pathway activation in E2/E2 neurons.

## Key findings

- Aβ induces 64 genes in M E2/E2 neurons and 44 genes in F E3/E3 neurons.
- Aβ-induced genes in M E2/E2 neurons activate inflammatory and cell migration pathways.
- Aβ-induced genes in F E3/E3 neurons do not form significant pathways.

## Abstract

The deposition of amyloid beta (Aβ) in the human brain is a hallmark of Alzheimer’s disease (AD). Aβ has been shown to exert a wide range of effects on neurons in cell and animal models. Here, we take advantage of differentiated neurons from iPSC-derived neural stem cells of human donors to examine its effects on human neurons. Specifically, we employed two types of neurons from genetically distinct donors: one male carrying APO E2/E2 (M E2/E2) and one female carrying APO E3/E3 (F E3/E3). Genome-wide RNA-sequencing analysis identified 64 and 44 genes that were induced by Aβ in M E2/E2 and F E3/E3 neurons, respectively. GO and pathway analyses showed that Aβ-induced genes in F E3/E3 neurons do not constitute any statistically significant pathways whereas Aβ-induced genes in M E2/E2 neurons constitute a complex network of activated pathways. These pathways include those promoting inflammatory responses, such as IL1β, IL4, and TNF, and those promoting cell migration and movement, such as chemotaxis, migration of cells, and cell movement. These results strongly suggest that the effects of Aβ on neurons are highly dependent on their genetic background and that Aβ can promote strong responses in inflammation and cell migration in some, but not all, neurons.