Microglia are the main immune cells of the central nervous system, and it is well known that these cells play an important role in neuroinflammation and are involved in many neurodegenerative diseases such as Alzheimer disease (AD). Human iPSC-derived microglia from healthy individuals and AD patients provide new tools to better study microglial response in AD.
Human iPSC-derived microglia, showing inflammatory responses comparable to in vivo microglia, can be used as an in vitro model to study neuroinflammation with high translational relevance.
Stimulation with pre-aggregated Aβ1-42 results in increased IL-8 levels in the supernatant of differentiated human iPSC-derived microglia from healthy individuals and even stronger from individuals with AD (Figure 1A). Levels of IL-1β were at the same time strongly decreased in the supernatant of human iPSC-derived microglia from AD patients (Figure 1B).
Figure 1: Quantification of IL-8 and IL-1β levels in the supernatant of Aβ1-42-stimulated healthy and Alzheimer’s disease (AD) patients’ microglia. Differentiated human iPSC-derived microglia treated with vehicle (VC), 10 µM monomeric Aβ1-42 or 10 µM pre-aggregated Aβ1-42. IL-8 (A) andIL-1β (B) levels were measured. Mean+ SEM (n = 6 per group). Two-way ANOVA, followed by Bonferroni’s post hoc test compared to VC. ***p<0.001 between treatment groups and ###p<0.001 Healthy vs. AD.
Also in more general settings, assessing the response of differentiated iPSC-derived human microglia to the strong pro-inflammatory stimulus LPS for 24 h resulted in an increased secretion of relevant cytokines (Figure 2). This increase can be reversed by reference items like dexamethasone (Dexa; Figure 2), providing a fast and reproducible screening tool for anti-inflammatory drugs.
Figure 2: Increased cytokine release in LPS-stimulated iPSC-derived microglia can be reversed with dexamethasone treatment. After 24 h stimulation, supernatants were collected and analyzed for three cytokines IL-8, IL-6 and TNF-alpha. Data are shown as pg/mL supernatant. Mean+SEM, n=4-7 per group. One-way ANOVA with Bonferroni post hoc test. *p<0.05; **p<0.01. Dexa, dexamethasone; LPS, lipopolysaccharide; VC, vehicle control.
The same cells can also be used to assess phagocytosis modulators.
Human iPSC-derived microglia are therefore a valuable tool to study neuroinflammatory processes and alterations. The ability to use human-derived healthy and diseased cells opens a great opportunity to test the response of microglia-targeted treatments in vitro.