ArticlePloS one2020
Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2.
Article in PloS one, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Pooled it
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- Variant-to-function dissection of the 17q21.31 locus resolves ANKRD1 as a convergent regulatory target.BMC medical genomics · 2026Article
- T1WI-SWI Dual Modal Magnetic Resonance Nanoprobes for Accurate Diagnosis of Early Stage Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The curious case of a heterozygous loss-of-functionMolecular neurodegeneration advances · 2025Article
- Differential allelic representation (DAR) identifies candidate eQTLs and improves transcriptome analysis.PLoS computational biology · 2024Article
- AgeAnnoMO: a knowledgebase of multi-omics annotation for animal aging.Nucleic acids research · 2024Article
- Zebrafish as a Model Organism for Studying Pathologic Mechanisms of Neurodegenerative Diseases and other Neural Disorders.Cellular and molecular neurobiology · 2023Review
- Article
- Cracking the Code of Neuronal Cell Fate.Cells · 2023Review
- Use of Zebrafish Genetic Models to Study Etiology of the Amyloid-Beta and Neurofibrillary Tangle Pathways in Alzheimer's Disease.Current neuropharmacology · 2022Review
- Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism.Disease models & mechanisms · 2022Article
- Mitochondrial dysfunction-induced H3K27 hyperacetylation perturbs enhancers in Parkinson's disease.JCI insight · 2021Article
- Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.Aging · 2021Article
- No observed effect on brain vasculature of Alzheimer's disease-related mutations in the zebrafish presenilin 1 gene.Molecular brain · 2021Article
- Unearthing of Key Genes Driving the Pathogenesis of Alzheimer's Disease via Bioinformatics.Frontiers in genetics · 2021Article
- Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery.Frontiers in pharmacology · 2021Review
- Zebrafish Chromosome 14 Gene Differential Expression in theFrontiers in genetics · 2021Article
- Accelerated loss of hypoxia response in zebrafish with familial Alzheimer's disease-like mutation of presenilin 1.Human molecular genetics · 2020Article
- Environmental Enrichment Improved Learning and Memory, Increased Telencephalic Cell Proliferation, and Induced Differential Gene Expression inFrontiers in pharmacology · 2020Article
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains.
methodsWe edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD.
resultsYoung heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional 'inversion' that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aβ.
conclusionsOur results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.