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bioRxiv2024

Ethanol exposure model in zebrafish causes phenotypic, behavioral and gene expression changes that mimic Fetal Alcohol Spectrum Disorders in human birth cohorts

Fetal Alcohol Spectrum Disorders (FASD) represent a significant global health challenge, characterized by physical and neurodevelopmental abnormalities in offspring resulting from prenatal alcohol exposure. This study aims to utilize the zebrafish to examine the phenotypic, behavioral, and molecular changes associated with embryonic ethanol exposure, providing a model for human FASD conditions. Our study exposed zebrafish embryos to 0.5% ethanol during a critical developmental window (2-24 hours post-fertilization) and documented significant craniofacial and cardiac deformities, which recapitulate what has been observed in human FASD in humans. Notably, exposed zebrafish exhibited reduced skull and eye sizes, thickened jaw size, and enlarged heart chambers. We found reduced burst swim distance following a touch stimulus, a novel behavioral assessment of potential deficits in sensory processing such as processing speed and/or stress/startle response, both of which are affected in human FASD. Whole-organism gene expression was found to be altered by ethanol for orthologs of four of five inflammation-related genes for which placental expression was previously found to be altered in response to alcohol in human placentas (SERPINE1, CRHB, BCL2L1, PSMB4, PTGS2A). We conclude that the zebrafish model effectively mimics several FASD phenotypes observed in humans, confirming gene expression changes we have previously documented in a human observational study and providing a valuable platform for exploring the underlying mechanisms of alcohol-induced embryonic alterations and for developing diagnostic markers and therapeutic targets for early intervention.

pathology↗

bioRxiv2022

Neurogenic induction by Ngfr reduces reactive astrocytic Lcn2/Slc22a17 signalling, amyloid deposition and Tau phosphorylation

Neurogenesis relates to the brain resilience and is reduced in Alzheimers disease (AD). Restoring healthy levels of neurogenesis could have beneficial effects for coping with neurodegeneration. However, molecular mechanisms that could enhance neurogenesis from astroglial progenitors in AD pathology are largely unknown. We used lentiviruses to express Ngfr in the hippocampus of the APP/PS1dE9 mouse model of AD, histologically analyzed the changes in proliferation of neural stem cells and neurogenesis; performed single-cell transcriptomics, spatial proteomics, and functional knockdown studies. We found that expression of Ngfr, a neurogenic determinant in pathology-induced neuroregeneration in zebrafish, stimulated proliferative and neurogenic outcome in the APP/PS1dE9 AD mouse model. Ngfr suppressed reactive astrocyte marker Lipocalin-2 (Lcn2) in astroglia. Blockage of Lcn2 receptor, Slc22a17, recapitulated the neurogenic effects of NGFR, and long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Furthermore, immunostaining on postmortem human hippocampi with AD or primary age-related Tauopathy and 3D human astroglial cultures showed that elevated LCN2 levels correlate with gliosis. By comparing transcriptional changes in mouse hippocampus, zebrafish brain, and human AD brains in terms of cell intrinsic differential gene expression analyses as well as weighted gene co-expression network analysis, we observed common potential downstream effectors of NGFR signaling, C4B and PFKP, that are relevant to AD. Our study links the regulatory role of an autocrine molecular mechanism in astroglia to the neurogenic ability and modulatory effects on amyloid and tau phosphorylation, opening new research avenues and suggesting that neurogenesis-oriented therapeutic approaches could be a potential clinical intervention for AD.

neuroscience↗