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Fibrillar ?-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation.

ABSTRACT: 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) (A?f, A?O) or to conditioned medium from human primary microglia activated with either A?(1-42) or lipopolysaccharide. The neurospheres were differentiated for 29 days 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 A?f, but not A?O, increased the secretion of IL-6, IL-1? and IL-2. A?f 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 A?f, demonstrating decreased secretion of TNF-?, IL-1? and IL-2 relative to untreated cells. Subsequent exposure of differentiating neurospheres to A?f 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 A?f decreases neurogenesis by promoting a microenvironment favouring hypo-cholinergic signalling and gliogenesis.

SUBMITTER: Malmsten L

PROVIDER: S-EPMC4196662 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Fibrillar β-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation.

Malmsten Linn L Vijayaraghavan Swetha S Hovatta Outi O Marutle Amelia A Darreh-Shori Taher T

Journal of cellular and molecular medicine 20140811 9

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 (Aβ)-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 Aβ(1-42) (Aβf, AβO) or to conditioned medi ...[more]

PMID: 25109373

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Project description:IntroductionNeuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.MethodsWe used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of AD at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.ResultsWe identified a pattern of up-regulated IFNγ, IP-10/CXCL10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.ConclusionsWe identify a pattern of cytokine secretion predictive of progressing amyloid-β pathology in the 5xFAD mouse model of AD that reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in AD.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-023-00782-y.

Project description:Amyloid-? peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-?. The amyloid-? hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-? oligomers or fibrillar deposits. Apolipoprotein-?4 (APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-? interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BA?ACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine-synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular ?4 isoprotein acts as one of the strongest endogenous anti-amyloid-? fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-? fibrillization for at least 65 h. We show that amyloid-? interacts readily in an apolipoprotein-facilitated manner with butyrylcholinesterase, forming highly stable and soluble complexes, BA?ACs, which can be separated in their native states by sucrose density gradient technique. Enzymological analyses further evinced that amyloid-? concentration dependently increased the acetylcholine-hydrolyzing capacity of cholinesterases. In silico biomolecular analysis further deciphered the allosteric amino acid fingerprint of the amyloid-?-cholinesterase molecular interaction in formation of BA?ACs. In the case of butyrylcholinesterase, the results indicated that amyloid-? interacts with a putative activation site at the mouth of its catalytic tunnel, most likely leading to increased acetylcholine influx into the catalytic site, and thereby increasing the intrinsic catalytic rate of butyrylcholinesterase. In conclusion, at least one of the native physiological functions of amyloid-? is allosteric modulation of the intrinsic catalytic efficiency of cholinesterases, and thereby regulation of synaptic and extrasynaptic cholinergic signalling. High apolipoprotein-E may pathologically alter the biodynamics of this amyloid-? function.

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Fibrillar ?-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation.

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Fibrillar β-amyloid 1-42 alters cytokine secretion, cholinergic signalling and neuronal differentiation.

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