Author:
Konstantinidis Evangelos,Portal Benjamin,Mothes Tobias,Beretta Chiara,Lindskog Maria,Erlandsson Anna
Abstract
Abstract
Background
Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated.
Methods
In this study, we aimed to investigate how intracellular deposits of Aβ in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils. The direct and indirect effects of the Αβ-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte–neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.
Results
Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with Aβ-exposed astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with Aβ deposits led to an elevated clearance of dead cells in the co-cultures.
Conclusions
Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactive state of the astrocytes, as well as their ability to support neuronal function.
Funder
Vetenskapsrådet
Alzheimerfonden
Åhlén-stiftelsen
Hjärnfonden
O. E. och Edla Johanssons Vetenskapliga Stiftelse
Stiftelsen Olle Engkvist Byggmästare
Bertil and Ebon Norlin stiftelse
Gun och Bertil Stohnes Stiftelse
Uppsala University
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
Reference63 articles.
1. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.
2. Hanslik KL, Marino KM, Ulland TK. Modulation of glial function in health, aging, and neurodegenerative disease. Front Cell Neurosci. 2021;15:718324.
3. Stevenson R, Samokhina E, Rossetti I, Morley JW, Buskila Y. Neuromodulation of glial function during neurodegeneration. Front Cell Neurosci. 2020;14:278.
4. Kumar A, Fontana IC, Nordberg A. Reactive astrogliosis: a friend or foe in the pathogenesis of Alzheimer’s disease. J Neurochem. 2021;00:1–16.
5. Webers A, Heneka MT, Gleeson PA. The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer’s disease. Immunol Cell Biol. 2020;98:28–41.
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献