# Presenilin 1 E280A mutation induces dysfunctional astrocytic phenotype in menstrual stromal-derived astrocyte-like cells

## TL;DR

This study shows that astrocyte-like cells derived from menstrual stromal cells with a PSEN1 E280A mutation exhibit dysfunctional traits linked to Alzheimer's disease, making them a useful model for studying the condition.

## Contribution

The study introduces a novel in vitro model using menstrual stromal-derived astrocyte-like cells to investigate the role of astrocytes in familial Alzheimer's disease.

## Key findings

- PSEN1 E280A astrocyte-like cells showed a 3900% increase in intracellular amyloid beta and a 70% reduction in phagocytosis activity.
- These cells had a 543% increase in autophagosomes and a 37% increase in NF-κB activation, indicating dysregulated cellular processes.
- They secreted high levels of extracellular Aβ42 (~57 pg/mL) and IL-6, suggesting a pro-inflammatory state.

## Abstract

Familial Alzheimer’s disease (FAD) is a progressive neurodegenerative disorder associated with loss of cholinergic neurons, intra- and extracellular accumulation of amyloid beta (iAβ, eAβ), hyperphosphorylated tau, and neuroinflammation i.e., reactive glia. The precise contribution of astrocytes to neurodegeneration in FAD is still incompletely understood. Therefore, there is a need for a reliable and simple in vitro cell culture model of neuroinflammation. The aim of the present investigation was to determine the pathophysiological behavior of astrocyte-like cells (ALCs) derived from wild-type (WT) and PSEN1 E280A menstrual stromal cells (MenSCs). We found that WT and PSEN1 E280A MenSCs displayed similar cellular mesenchymal lineage markers and similar capacity to differentiate into mesenchymal lineage osteocytes, adipocytes, and chondrocytes. In addition, WT and mutant ALCs exhibited similar percentages of astrocyte lineage markers such as GFAP+ (~ 90%) and S100β+ (70%). However, compared to WT ALCs, PSEN1 E280A ALCs (i) showed a complete lack of response to Glu-induced Ca2+ influx; (ii) presented a high percentage of iAβ-positive cells (+ 3900% increase); (iii) exhibited a markedly dysfunctional phagocytosis activity (-70% reduction); (iv) revealed a dysregulation of apoptotic body clearance (-64% Lysotracker+/PI + cells); (v) showed abnormal accumulation of autophagosomes (+ 543% LC3-II + cells); (vi) revealed an increased TNF-α-induced activation of NF-κB (+ 37% MFI increase); (vii) an increased secretion of IL-6 (+ 160%), and (viii) secreted high amounts of Aβ42 (extracellular Aβ42, ~ 57 pg/mL). Notably, there was no change in TREM2 expression, mitochondrial membrane potential (ΔΨm, 100%), or induced cleaved caspase 3 (CC3, 0%) in PSEN1 E280A and WT ALCs. These findings highlight the importance of MenSCs-derived ALCs as a promising model to study the pathophysiological basis of FAD.