New Human IPSC Models of Late-onset Alzheimer's Disease Polygenic Risk Identify Multiple Impairments of Microglial Function
Hall-Roberts, H.; Maguire, E.; Shaw, B.; O'Donoghue, R.; Winston, J.; Keat, S.; Capitani, L.; Mahoney, R.; Geary, B.; Faber, K.; Stöberl, N.; Connor-Robson, N.; Bridge, C.; Castillo Morales, A.; Bernado-Harrington, M.; Allen, N. D.; Escott-Price, V.; Webber, C.; Cowley, S. A.; Taylor, P. R.; Holmans, P.; Sims, R.; Williams, J.
Show abstract
Genetic discoveries implicate microglia in late-onset Alzheimers disease (AD). We modelled AD in a powerful study of 51 human induced pluripotent stem cell (iPSC) microglia derived from high-polygenic risk AD or low-risk cognitively well individuals, sampled from a large cohort. We explored mitochondrial function, cytokine secretion, endocytosis, phagocytosis, lipid accumulation, calcium store release, and chemotaxis under basal conditions and immune challenge. High polygenic risk was independently associated with significant functional deficits in iPSC microglia under immune challenge, in mitochondrial ATP production (p=0.005, -13%), and inflammatory cytokine release (IL-6: p=0.018, -42%; TNF p=0.026, -38.5%). Furthermore, a selective deficit in amyloid-{beta} uptake was identified (p=0.00477, -5.9%). Deficits in inflammatory cytokine release were driven by APOE {varepsilon}4. These findings reflect primary changes in AD pathogenesis predating plaque formation and validate a human in vitro platform for late-onset AD to further understand disease mechanisms and screen drug or genetic therapies.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Microglia initially seed and later reshape amyloid plaques in Alzheimer's disease 96%
- Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy 96%
- Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy 96%
Similar papers in this journal
- Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease 97%
- Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer's disease 97%
- Applying high-resolution spatial transcriptomics to characterise the amyloid plaque cell niche in Alzheimer's Disease 96%
Similar papers in this journal
- Glucose hypometabolism and hyperphosphorylated Tau synergistically drive neuronal necroptosis 95%
- Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model 95%
- The Alzheimers Disease Risk Genes MS4A4A And MS4A6A Cooperate to Negatively Regulate Trem2 and Microglia states 95%
Similar papers in this journal
Similar papers in this journal
- Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity 96%
- Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis 93%
- Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to the human brain evolution 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.