# Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS

## TL;DR

This paper introduces a new human microglia aging model that shows aged microglia contribute to brain aging and neurodegeneration by impairing stress response and protein transport.

## Contribution

A novel human in vitro model of microglial aging using progerin expression is developed to study age-related neurodegeneration.

## Key findings

- Prematurely aged microglia show reduced LPS response, migration, and phagocytosis.
- Aged microglia exhibit impaired nucleocytoplasmic transport of ALS-associated FUS protein.
- Senolytic treatments partially reverse some aging markers in the model.

## Abstract

Microglia, the brain's resident immune cells, are crucial for maintaining healthy brain homeostasis. However, as the brain ages, microglia can shift from a neuroprotective to a neurotoxic phenotype, contributing to chronic inflammation and promoting neurodegenerative processes. Despite the importance of understanding microglial aging, there are currently few human in vitro models to study these processes. To address this gap, we have developed a model in which human microglia undergo accelerated aging through inducible progerin expression. HMC3‐Progerin cells display key age‐related markers such as activation of the senescence‐associated secretory phenotype (SASP) as well as an increase in DNA damage. These prematurely aged HMC3 cells show a reduced response to LPS activation, exhibit impairments in essential microglial functions including decreased migration and phagocytosis as well as transcriptomic alterations including a shift observed in aging and neurodegeneration. Additionally, we observed an impaired stress response and a defect in nucleocytoplasmic transport, especially affecting the amyotrophic lateral sclerosis (ALS) associated protein FUS. This suggests that microglia play a contributory role in driving neurodegenerative processes in the aging brain. Our microglia aging model offers a valuable tool for exploring how aged microglia affect brain function, enhancing our understanding of their role in brain aging.

We developed a human microglia aging model by doxycycline‐induced GFP‐progerin expression, which offers a valuable tool to study human microglial aging and its contribution to neurodegeneration. Induced HMC3‐Progerin cells exhibited increased age markers as well as transcriptomic alterations, including an age‐associated transcriptomic shift and overlapping signatures observed in aging and neurodegeneration, as well as functional alterations (e.g., in stress response, defect in nucleocytoplasmic transport). Senolytic treatments partially reversed some age markers.