Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 18, Issue 9, Pages 1874-1888Publisher
WILEY
DOI: 10.1111/jcmm.12343
Keywords
human microglia; Alzheimer's disease; inflammation; neurospheres; human embryonic stem cells; neurogenesis; gliogenesis
Categories
Funding
- Swedish Medical Research Council [05817]
- Stockholm County Council-Karolinska Institutet (ALF)
- Karolinska Institutet Strategic Neuroscience Program
- Brain Foundation
- Gun and Bertil Stohne's Foundation
- Foundation for Old Servants
- Magnus Bergvall's Foundation
- Dementia Association
- Lars Hierta Memorial Foundation
- Olle Engkvist Byggmastare Foundation
- Ake Wiberg Foundation
- Sigurd and Elsa Golje's Memory Foundation
- Ahlen Foundation
- Karolinska Institutet Foundations
- Alzheimer Association Sweden
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Adult neurogenesis is impaired by inflammatory processes, which are linked to altered cholinergic signalling and cognitive decline in Alzheimer's disease. In this study, we investigated how amyloid beta (A)-evoked inflammatory responses affect the generation of new neurons from human embryonic stem (hES) cells and the role of cholinergic signalling in regulating this process. The hES were cultured as neurospheres and exposed to fibrillar and oligomeric A(1-42) (Af, AO) or to conditioned medium from human primary microglia activated with either A(1-42) or lipopolysaccharide. The neurospheres were differentiated for 29days in vitro and the resulting neuronal or glial phenotypes were thereafter assessed. Secretion of cytokines and the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and choline acetyltransferase (ChAT) involved in cholinergic signalling was measured in medium throughout the differentiation. We report that differentiating neurospheres released various cytokines, and exposure to Af, but not AO, increased the secretion of IL-6, IL-1 and IL-2. Af also influenced the levels of AChE, BuChE and ChAT in favour of a low level of acetylcholine. These changes were linked to an altered secretion pattern of cytokines. A different pattern was observed in microglia activated by Af, demonstrating decreased secretion of TNF-, IL-1 and IL-2 relative to untreated cells. Subsequent exposure of differentiating neurospheres to Af or to microglia-conditioned medium decreased neuronal differentiation and increased glial differentiation. We suggest that a basal physiological secretion of cytokines is involved in shaping the differentiation of neurospheres and that Af decreases neurogenesis by promoting a microenvironment favouring hypo-cholinergic signalling and gliogenesis.
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