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Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart diseases. To elucidate the cardiac myocyte specific effects of PSEN ΔE9, we studied cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from patients carrying AD-causing PSEN1 exon 9 deletion (PSEN1 ΔE9). When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased sarcoplasmic reticulum (SR) Ca 2+ leak that was resistant to blockage of ryanodine receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP 3 Rs) by 2-ABP. The SR Ca 2+ leak did not affect electrophysiological properties of the hiPSC-CMs, but according to experiments and in silico simulations the leak induces a diastolic buildup of [Ca 2+ ] near the perinuclear SR and reduces the releasable Ca 2+ during systole. This demonstrates that PSEN1 ΔE9 induced SR Ca 2+ leak has specific effects in iPSC-CMs, reflecting their unique structural and calcium signaling features. The results shed light on the physiological and pathological mechanisms of PSEN1 in cardiac myocytes and explain the intricacies of comorbidity associated with AD-causing mutations in PSEN1., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca 2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood-brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.

A double mutation (KM670/671NL) in amyloid precursor protein gene (APP) is causative for familial Alzheimer's disease and has been shown to increase the total Aβ burden. Here we report the generation and characterization of an iPSC line from a fAD patient carrying APP KM670/671NL. The generated iPSCs retained the mutation, expressed pluripotency markers, showed a normal karyotype and differentiated into all three germ layers. This iPSC line can be used, for example, in disease modeling and mechanistic studies. Resource table., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

An amyloid precursor protein (APP) A673T mutation was found to be protective against Alzheimer's disease (AD) and cognitive decline in the Icelandic population and to associate with decreased levels of plasma β-amyloid in a Finnish population-based cohort. Human fibroblasts from a Finnish male individual carrying the protective mutation were used to generate integration-free induced pluripotent stem cell (iPSCs) line by Sendai virus technology. The iPSC line retained the mutation and expressed pluripotency markers, had a normal karyotype and differentiated into all three germ layers., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Neural cells derived from human induced pluripotent stem cells (iPSCs) are innovative models for dissecting the pathological mechanisms of Alzheimer's disease (AD). However, in vitro differentiation of iPSCs to functional and mature neural cells is still not optimized. We generated/characterized iPSCs-derived neurons and astrocytes from controls and AD patients with PSEN1ΔE9 mutation. After one/two months of neurosphere differentiation, plated cells reached 30% of βIII-tubulin+ neurons with slightly higher levels of nitric oxide, compared to control. Astrocytes from astrospheres after five months of differentiation expressed S100B, but only 50% were GFAP+. AD astrocytes displayed a depressed functional phenotype with lower levels of miR-155 and RAGE mRNA, and released exosomes depleted in alarmins (HMGB1 and S100B). When stimulated to A1 inflammatory phenotype, these astrocytes acquired a fibroblast-like morphology and expressed elevated miR-155, when compared to control, while their exosomes contained increased levels of HMGB1 and S100B mRNA. Collectively, AD astrocytes differentiated from iPSCs reveal a deregulated inflammatory profile and a specific exosomal cargo. [ABSTRACT FROM AUTHOR]