# Glial and Neuronal Alzheimer's Disease-Related Alterations Reproduced in Human Induced Pluripotent Stem Cells With Presenilin-1 Mutation

## TL;DR

This study uses human stem cells with a PSEN1 mutation to model Alzheimer's-related changes in glial and neuronal cells, revealing how these changes contribute to neurodegeneration.

## Contribution

The study demonstrates that iPSC-derived glial and neuronal cells with PSEN1 mutations reproduce key Alzheimer's-related alterations and their interactions.

## Key findings

- AD iPSC-derived microglia show compromised function and astrocytes display a fibroblast-like, inflammatory phenotype.
- Glia-specific AD changes in cocultures lead to neuronal network degradation and synaptic impairments.
- Replacing AD glia with healthy glia does not prevent neurodegeneration, highlighting the role of PSEN1 mutations in neurons.

## Abstract

A pathogenetic role of glial cells has been established virtually in all neurodegenerative disorders. In Alzheimer's disease (AD), together with β-amyloid deposition and the formation of fibrillary tangles, neuroinflammation contributes to neuronal dysfunction associated with the disease. Thus, selective control of glial cell activation becomes part of the multifactorial therapeutic strategies in AD. Astrocytes and microglia are highly heterogeneous in their morphology and physiology, and this diversity underlies their distinct functional states in the central nervous system. In AD, they exhibit dynamic and stage-dependent pathological phenotypes during disease onset and progression. In this context, investigating the disease-associated glia signature would provide significant progress in understanding pathological mechanisms and in the development of beneficial treatments. The use of human induced pluripotent stem cells (iPSCs) to study CNS cell alterations during brain pathologies greatly improves the possibility of identifying human- and cell-specific changes likely contributing to AD progression.

Here we used isolated glia cultures and neuron/glia cocultures derived from iPSC carrying a mutation in the presenilin-1 (PSEN1) gene to investigate AD-related microglia and astrocyte impairments and their contribution to neuronal degeneration.

Microglia from AD iPSCs showed compromised functional properties while astrocytes exhibited a predominant fibroblast-like phenotype and increased expression of inflammatory markers. Consistently, transcriptomic derangement for reactive phenotype-related genes, correlating with cell morphology, allowed to well distinguish AD astrocytes from control cells. We finally observed that glia-specific AD-related changes affected some neuronal properties in mixed neuron/glia cocultures, while the presence of the mutation in both cell population triggered a dramatic neuronal damage, involving neuronal network degradation, synaptic alterations and impaired electrophysiological properties. On the other hand, the replacement of AD with healthy glia was not sufficient to protect from neurodegeneration, suggesting the pivotal role of mutated PSEN1 in neurons.

We herein succeeded in reproducing crucial AD-related changes in iPSC-derived in vitro models providing new insights in the neuropathological communication amongst brain cells, thus representing a promising tool to deepen disease mechanisms and develop neuroprotective treatments.