Biology subjects

Fassbender, K.

Publications and source records attributed to Fassbender, K..

3 recordsLinked to original sources

bioRxiv2023

Modulation of Alzheimer's Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88

Gut bacteria regulate brain pathology of Alzheimers disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene, or haploinsufficiency of MyD88 in microglia were treated with antibiotics-supplemented or normal drinking water for 2 months. Antibiotic treatment eradicated gut bacteria, particularly in the phyla Bacteroidetes and Firmicutes, and reduced Il-17a-expressing CD4-positive T lymphocytes. Deletion of gut bacteria inhibited inflammatory activation in the brain and microglia, and reduced cerebral A{beta} levels in APP-transgenic mice, which was abolished by deficiency of Il-17a or haploinsufficiency of MyD88 in microglia. As possible mechanisms regulating A{beta} pathology, deletion of gut bacteria inhibited {beta}-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, deletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a and microglial MyD88-involved signalling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology.

neuroscience↗

bioRxiv2022

GABAergic modulation of conflict adaptation and response inhibition

Adaptive behavior is only possible by stopping stereotypical actions to generate new plans according to internal goals. It is response inhibition --the ability to stop actions automatically triggered by exogenous cues-- that allows for the flexible interplay between bottom-up, stimulus driven behaviors, and top-down strategies. In addition to response inhibition, cognitive control draws on conflict adaptation, the facilitation of top-down actions following high conflict situations. It is currently unclear whether and how response inhibition and conflict adaptation depend on GABAergic signaling, the main inhibitory neurotransmitter in the human brain. Here, we applied a recently developed computational model (SERIA) to data from two studies (N=150 & 50) of healthy volunteers performing Simon and antisaccade tasks. One of these datasets was acquired under placebo-controlled pharmacological enhancement of GABAergic transmission (lorazepam, an allosteric modulator of the GABA-A receptor). Our model-based results suggest that enhanced GABA-A signaling boosts conflict adaptation but impairs response inhibition. More generally, our computational approach establishes a unified account of response inhibition and conflict adaptation in the Simon and antisaccade tasks and provides a novel tool for quantifying specific aspects of cognitive control and their modulation by pharmacology or disease. Author SummaryOur capacity to prepare for situations that afford conflicting responses (conflict adaptation) and to stop our immediate impulses in these scenarios (response inhibition) are the hallmark of cognitive control. As these abilities require both the stopping or slowing of response tendencies, a natural question is whether they are mediated by inhibitory neurotransmission in the brain. Here, we combined computational modeling with two experiments to investigate how conflict adaptation and response inhibition interact with each other (experiment 1) and how these are modulated by lorazepam (experiment 2), a positive modulator of the GABA-A receptor, one of the main inhibitory receptors in the human brain. Using our computational model to disentangle conflict adaptation and response inhibition, our results indicate that while lorazepam impaired response inhibition, it improved conflict adaptation. Thus, our results suggests that conflict adaptation is mediated by GABA-A neurotransmission.

neuroscience↗

bioRxiv2021

Deficiency of p38α-MAPK in myeloid cells ameliorates symptoms and pathology of APP-transgenic Alzheimer's disease mice

Microglial activation is a hall marker of Alzheimers disease (AD); its pathogenic role and regulating mechanisms are unclear. p38-MAPK, a stress-responding kinase, is activated in AD brain in early disease stages. In APP-transgenic mice, we deleted p38-MAPK in whole myeloid cells from birth or specifically in microglia from 9 months, and analysed AD pathology at the age of 4, 9 and 12 months. In both experimental settings, p38-MAPK deficiency decreased cerebral A{beta} and improved cognitive function of AD mice; however, p38-MAPK-deficient myeloid cells were more effective than p38-MAPK-deficient microglia in preventing AD pathogenesis. Deficiency of p38-MAPK in myeloid cells inhibited the inflammatory activation of individual microglia by 4 months, but enhanced it by 9 months. Inflammatory activation was essential for p38-MAPK deficiency to promote microglial internalization of A{beta}. Interestingly, p38-MAPK deficiency in peripheral myeloid cells reduced il-17a transcription in CD4-positive spleen cells. By cross-breeding APP-transgenic mice and IL-17a knockout mice, we further observed that IL-17a deficiency activated microglia and decreased A{beta} deposits in AD mouse brain. Thus, p38-MAPK deficiency in myeloid cells prevents AD pathogenesis, perhaps through reducing IL-17a-expressing T lymphocytes, and promoting A{beta} clearance in the brain. Our study supports p38-MAPK as a novel target for AD therapy.

neuroscience↗