Biology subjects

Christmann, A.

Publications and source records attributed to Christmann, A..

3 recordsLinked to original sources

bioRxiv2025

Early Aβ-induced changes in the enteric nervous system and gut: structure, function, and motility

Alzheimers disease is increasingly recognized as affecting not only the central nervous system but also the autonomic nervous system, comprising the enteric nervous system, and thus the gut. Given the structural and functional similarities between the enteric and central nervous system, including susceptibility to A{beta}, this study investigated the early and acute effects of monomeric A{beta} on primary enteric neurons in vitro and on intestinal motility ex vivo. Acute A{beta} application caused marked neuronal hyperexcitability, with increased spike frequencies and calcium influx, and led to enhanced intestinal contractility without altering frequency or timing. Prolonged 72-hour exposure did not induce cell death or apoptosis but significantly reduced neurite outgrowth and decreased synaptic markers and beta II tubulin. These findings suggest that acute A{beta} primarily drives the excitability of enteric neurons and intestinal motility, while prolonged exposure subsequently leads to structural and synaptic changes. Overall, the study points to early dysfunction of the enteric nervous system in Alzheimers disease and highlights the gut as a potential target for early interventions. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/678722v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18b5292org.highwire.dtl.DTLVardef@1da0ecforg.highwire.dtl.DTLVardef@1023b09org.highwire.dtl.DTLVardef@171e3fb_HPS_FORMAT_FIGEXP M_FIG C_FIG The pathology of Alzheimers disease is increasingly recognized in the enteric nervous system (ENS), suggesting an early contribution of the gut to the onset of the disease. This study investigated the acute and short-term effects of amyloid-{beta} (A{beta}) on intestinal motility and enteric neurons to elucidate early functional and structural changes beyond the brain. O_LIAcute A{beta} exposure enhanced intestinal contractility ex vivo. C_LIO_LIEnteric neurons showed hyperexcitability and increased Ca{superscript 2} influx. C_LIO_LIAfter 72 h, neuronal viability and apoptosis remained unaffected. C_LIO_LIProlonged exposure reduced neurite outgrowth and {beta}III-tubulin expression. C_LIO_LISynaptic density was significantly decreased. C_LI

neuroscience↗

bioRxiv2022

Enteric glia adopt an activated pro-inflammatory state in response to human and bacterial amyloids

Mounting evidence suggests a role for the microbiome-gut-brain axis in amyloid-associated neurodegeneration, but the pathogenic changes induced by amyloids in the gastro-intestinal tract remain elusive. To scrutinize the early response to amyloids of human and bacterial origin, we challenged primary murine myenteric networks with A{beta}1-42 (vs a scrambled version of A{beta}1-42) and curli (vs culture medium), respectively, and performed shotgun RNA sequencing. Both amyloid types induced a transcriptional signature of DNA damage and cell cycle dysregulation. Using in vitro neurosphere-derived cultures and in vivo amyloid injections we found that enteric glia and smooth muscle cells were the most responsive cell types, showing increased proliferation, {gamma}H2AX burden and SOD2 levels after amyloid challenge. Consistent with this activated state, we identified a pro-inflammatory hub in the transcriptional profile of amyloid-stimulated myenteric networks. Enteric glia were the principal source of the associated cytokines, and in vivo, this was accompanied by an influx of immune cells. Together, these results shed new light on the intrinsic vulnerability of ENS cells to both amyloid species and position enteric glial cell activation as an early driver of neurodegenerative disease progression. Significance statementThe increasing socio-economic impact of Alzheimers disease (AD), long sub-clinical disease progression window, and failure of drug candidates demand mechanistic insight into the early stages of disease development. Epidemiological associations and experimental studies in rodents suggest that the gut may be vulnerable to amyloids and mediate their transfer to the brain. However, whether and how amyloids induce local pathology in the gastro-intestinal wall is not known. We identified a pathogenic program that becomes activated in the gastro-intestinal tract after exposure to amyloid {beta} and curli (the main bacterial amyloid), and show that enteric glia are responsible for creating an amyloid-induced pro-inflammatory environment. This insight of an early response in a distant, more accessible organ than the brain, may have important implications for both disease diagnosis and therapy.

neuroscience↗

bioRxiv2020

Functional and molecular early enteric biomarkers for Parkinson's disease in mice and men

Parkinsons disease (PD) usually has a late clinical onset. The lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use an -synuclein-overexpressing transgenic (Th-1-SNCA-A30P) mouse model of PD to identify appropriate candidate markers in the gut for early stages of PD before hallmark symptoms begin to manifest. A30P mice did not show alterations in gait parameters at 2 months of age, and these mice were therefore defined as pre-symptomatic A30P mice (psA30P). We discovered early functional motility changes in the gut and early molecular dysregulations in the myenteric plexus of psA30P mice by comparative protein and miRNA profiling and cell culture experiments. We found that the proteins neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are potential biomarkers of early PD that may facilitate timely treatment and/or prevention of PD in men.

neuroscience↗