Source: University of Eastern Finland.
Summary: Researchers have discovered a direct association between astrocytes and Alzheimer’s disease. In a new study, researchers report astrocytes in the brains of Alzheimer’s patients produced significantly more amyloid beta than astrocytes in the brains of people without the disease.
Representative immunocytochemistry images of astrocytes from control, AD, and isogenic control lines matured with CNTF and BMP4 for 7 days, stained for S100β (green) and GFAP (red). Nuclei are stained with Hoechst. Scale bars, 50 μm. NeuroscienceNews.com image is credited to Oksanen et al./Stem Cell Reports.
Astrocytes, the supporting cells of the brain, could play a significant role in the pathogenesis of Alzheimer’s disease (AD), according to a new study from the University of Eastern Finland. This is the first time researchers discovered a direct association between astrocytes and AD. Published in Stem Cell Reports, the study investigated the brain cell function of familial AD patients by using stem cell technologies.
Alzheimer’s disease is the most common dementia type, with no treatment to slow down the progression of the disease currently available. The mechanisms of AD are poorly understood, and drug therapy has focused on restoring the normal function of neurons and microglia, i.e. cells mediating brain inflammation. The new study shows that astrocytes, also known as the housekeeping cells of the brain, promote the decline of neuron function in AD. The findings suggest that at least some familial forms of AD are strongly associated with irregular astrocyte function, which promotes brain inflammation and weakens neurons’ energy production and signalling.
Astrocytes are important brain cells, as they support neurons in many different ways. Astrocytes are responsible, for example, for the energy production of the brain, ion and pH balance, and they regulate synapse formation, the connections between neurons. Recent evidence suggests that human astrocytes are very different from their rodent counterparts and thus, it would be essential to use human cells to study human diseases.
However, the availability of human astrocytes for research has been very limited. The study carried out at the University of Eastern Finland used the induced pluripotent stem cell technology, which enables the generation of pluripotent stem cells from human skin fibroblasts. These induced stem cells can then be further differentiated to brain cells, e.g. neurons and astrocytes, with the same genetic background as the donor had.
The study compared astrocytes from familial AD patients carrying a mutation in the presenilin 1 gene to astrocytes from healthy donors, and the effects of these cells on healthy neurons were also analysed.
The researchers found out that astrocytes in patients with Alzheimer’s disease produced significantly more beta-amyloid than astrocytes in persons without AD. Beta-amyloid is a toxic protein that is known to accumulate in the brains of AD patients.
In addition, AD astrocytes secreted more cytokines, which are thought to mediate inflammation. AD astrocytes also showed alterations in their energy metabolism which likely led to increased production of reactive oxygen species and reduced production of lactate, an important energy substrate for neurons. Finally, when astrocytes were co-cultured with healthy neurons, AD astrocytes caused significant changes on the signalling activity of neurons when compared to healthy astrocytes.
This study was the first to show that astrocytes in patients with Alzheimer’s disease manifest many pathological changes typical of AD. Astrocytes could thus play a key role in the early stages of the disease and changes in the function of these cells could lead to neurodegeneration.
“The induced pluripotent stem cells we used in this study proved to be extremely useful in disease modelling, and they could offer an excellent platform for drug discovery and testing new therapeutic targets for Alzheimer’s disease in the future,” says Early Stage Researcher Minna Oksanen, the lead author of the study.
Funding: This study was conducted at the University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, in Professor Jari Koistinaho’s research group in collaboration with the University of Turku and the University of Wisconsin-Madison. The research consortium was supported by JPND-CO-FUND funding via the Academy of Finland.
Source: Minna Oksanen – University of Eastern Finland
Image Source: NeuroscienceNews.com image is credited to Oksanen et al./Stem Cell Reports..
Original Research: Full open access research for “PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease” by Minna Oksanen, Andrew J. Petersen, Nikolay Naumenko, Katja Puttonen, Šárka Lehtonen, Max Gubert Olivé, Anastasia Shakirzyanova, Stina Leskelä, Timo Sarajärvi, Matti Viitanen, Juha O. Rinne, Mikko Hiltunen, Annakaisa Haapasalo, Rashid Giniatullin, Pasi Tavi, Su-Chun Zhang, Katja M. Kanninen, Riikka H. Hämäläinen, Jari Koistinaho in Stem Cell Reports. Published online November 16 2017 doi:10.1016/j.stemcr.2017.10.016
Abstract
PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease
Highlights
•PSEN1 mutant AD astrocytes manifest hallmarks of AD pathology
•Altered mitochondrial metabolism in AD astrocytes increases oxidative stress
•AD astrocytes reduce the calcium signaling activity of healthy neurons
•Astrocytes are important in the pathogenesis of AD
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.
“PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease” by Minna Oksanen, Andrew J. Petersen, Nikolay Naumenko, Katja Puttonen, Šárka Lehtonen, Max Gubert Olivé, Anastasia Shakirzyanova, Stina Leskelä, Timo Sarajärvi, Matti Viitanen, Juha O. Rinne, Mikko Hiltunen, Annakaisa Haapasalo, Rashid Giniatullin, Pasi Tavi, Su-Chun Zhang, Katja M. Kanninen, Riikka H. Hämäläinen, Jari Koistinaho in Stem Cell Reports. Published online November 16 2017 doi:10.1016/j.stemcr.2017.10.016
http://neurosciencenews.com/alzheimers-astrocytes-7967/
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