PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease

Abstract

Summary: Alzheimer's disease (AD) is a common neurodegenerative disorder and the leading cause of cognitive impairment. Due to insufficient understanding of the disease mechanisms, there are no efficient therapies for AD. Most studies have focused on neuronal cells, but astrocytes have also been suggested to contribute to AD pathology. We describe here the generation of functional astrocytes from induced pluripotent stem cells (iPSCs) derived from AD patients with PSEN1 ΔE9 mutation, as well as healthy and gene-corrected isogenic controls. AD astrocytes manifest hallmarks of disease pathology, including increased β-amyloid production, altered cytokine release, and dysregulated Ca2+ homeostasis. Furthermore, due to altered metabolism, AD astrocytes show increased oxidative stress and reduced lactate secretion, as well as compromised neuronal supportive function, as evidenced by altering Ca2+ transients in healthy neurons. Our results reveal an important role for astrocytes in AD pathology and highlight the strength of iPSC-derived models for brain diseases. : In this article, Koistinaho and colleagues reveal that astrocytes from PSEN1 ΔE9 patients display a severe AD-related phenotype, including increased Aβ production, altered mitochondrial metabolism, and reduced lactate secretion. Furthermore, PSEN1 ΔE9 astrocytes influence the calcium signaling activity of healthy neurons. The results highlight the importance of astrocytes in AD pathogenesis. Keywords: β-amyloid production, cytokine release, calcium homeostasis, mitochondrial metabolism, oxidative stress, lactate secretion