Dysregulated ac4C modification of mRNA in a mouse model of early-stage Alzheimer’s disease

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 13, 2025

The identification and intervention of Alzheimer's Disease (AD) in its early-stage allows for the timely implementation lifestyle modifications therapeutic strategies. Although dysregulation protein expression has been reported brain from AD patients animal models, underlying mechanisms remain poorly understood. N4-acetylcytidine (ac4C), only known form RNA acetylation eukaryotes, recently shown to regulate mRNA stability translation efficiency. However, ac4C associated with abnormal levels mouse models remains be elucidated. This study investigated modifications, hippocampus 3 6-month-old 5×FAD mice, a model AD, wild-type (WT) littermates. multi-omics analysis was performed: acetylated immunoprecipitation followed by next-generation sequencing (acRIP-seq) identify mRNAs, deep (RNA-seq) quantify abundance, label-free quantitative proteomics assess levels. In addition, we used acRIP-qPCR, regular qPCR western blots verify ac4C, some key genes that were identified high-throughput assays. Proteomic revealed significant change 3-months-old compared WT contrast, RNA-seq indicated there no substantial alterations Strikingly, acRIP-seq notable variations modification on particularly those synaptic structure function, found correlated changes. Genes are essential function cognition, including GRIN1, MAP2, DNAJC6, exhibited reduced without any corresponding changes levels, Moreover, small part dysregulated mRNAs 3-month-old mice mice. Altogether these results may contribute synthesis an AD.

Language: Английский

Human iPSC-RPE with the PSEN1H163R pathogenic variant recapitulates Alzheimer’s disease features and reveals melanosome defects

Published: May 12, 2025

Background Alzheimer’s disease (AD) is characterised by progressive cognitive decline and accumulation of pathological markers such as β-amyloid (Aβ) plaques Tau tangles. Emerging evidence suggests these can also be detected in the retina, positioning it a potential surrogate for investigating AD pathophysiology. The retinal pigment epithelium (RPE) shares features with brain critical health, yet its role pathology remains underexplored. Methods We generated RPE cells from human induced pluripotent stem carrying PSEN1^H163R pathogenic variant AD, alongside CRISPR-corrected isogenic control. AD-associated phenotypes were assessed. Results cell cultures two cohorts displayed expression Aβ Tau, notable differences levels organisation. Total Aβ₁₋₄₂ Aβ_{1−42:1−40} ratio lysates significantly elevated compared to CRISPR controls volume Aβ⁺ deposits was larger cells. phosphorylated proteins both cohorts, altered spatial organisation localisation pTau PSEN1^H163R. Proteomic profiling identified more than 1,800 dysregulated cells, including key AD-related MAPT, APP, APBB1 NRBF2. Upregulated pathways involved autophagy, intracellular trafficking neurodegeneration, while downregulated implicated mitochondrial respiration, RNA metabolism, protein folding. Proteomics analysis conditioned media further revealed secretion matrix-associated well increased APOE APP samples.PSEN1^H163R demonstrated dysregulation melanosome biogenesis, marked decreased core melanogenic (PMEL, TYR, DCT) proteomics analysis; morphology pigmentation electron microscopy. Conclusion In conclusion, findings support relevant accessible in vitro model research, offering insights into PSEN1 dysregulation, mechanisms providing promising approach understand biology context biomarker discovery. It first describe relationship between melanosomes cellular model.

Language: Английский

Key genes and pathways in asparagine metabolism in Alzheimer’s Disease: a bioinformatics approach

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Abstract Background Asparagine (Asn) metabolism is essential for maintaining cellular homeostasis and supporting neuronal energy demands. Recent studies have suggested its dysregulation may contribute to Alzheimer’s disease (AD) pathogenesis; however, the specific genes regulatory mechanisms involved remain incompletely understood. Methods Four publicly available microarray datasets (GSE5281, GSE29378, GSE36980, GSE138260) were utilized investigate with differential expression between control AD samples. metabolism-related (AMGs) retrieved from GeneCards database, their intersection DEGs yielded candidate asparagine differentially expressed (AMG-DEGs). Functional enrichment analysis (Gene Set Enrichment Analysis, Gene Ontology Kyoto Encyclopedia of Genes Genomes), protein–protein interaction (PPI) network analysis, centrality scoring identified hub genes. Regulatory investigated through construction competing endogenous RNA transcription factor networks. Potential therapeutic compounds predicted via drug–gene evaluated using molecular docking simulations. Results Thirty-nine AMG-DEGs found be enriched in neurodevelopmental, synaptic transmission, inflammatory signaling pathways. PPI screening revealed seven ( HPRT1 , GAD2 TUBB3 GFAP CD44 CCL2 NFKBIA ). highlighted miRNAs, long non-coding RNAs, factors modulation. Drug Bathocuproine disulfonate, DL-Mevalonic acid, Phenethyl isothiocyanate as promising strong binding affinities proteins. Conclusion This study comprehensively maps reveals a set elements potentially progression. The provide foundation further experimental validation development novel metabolism-targeted strategies treatment.

Language: Английский