Dataset Information

APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

ABSTRACT: A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated β-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

SUBMITTER: Perez-Corredor P

PROVIDER: S-EPMC10987717 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

Perez-Corredor Paula P Vanderleest Timothy E TE Vacano Guido N GN Sanchez Justin S JS Villalba-Moreno Nelson D ND Marino Claudia C Krasemann Susanne S Mendivil-Perez Miguel A MA Aguillón David D Jiménez-Del-Río Marlene M Baena Ana A Sepulveda-Falla Diego D Lopera Francisco F Quiroz Yakeel T YT Arboleda-Velasquez Joseph F JF Mazzarino Randall C RC

Frontiers in molecular neuroscience 20240320

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modula ...[more]

PMID: 38571814

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Project description:Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimer's disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells. In order to profile shifting microglial states in early AD and identify microglia-specific drivers of disease, we differentiated human induced pluripotent stem cells (iPSCs) carrying a familial AD PSEN2 mutation or its isogenic control into cerebral organoids and quantified the changes in cytokine concentrations over time with Luminex XMAP technology. We used partial least squares (PLS) modeling to build cytokine signatures predictive of disease and age to identify key differential patterns of cytokine expression that inform the overall organoid immune milieu and quantified the corresponding changes in protein pathology. AD organoids exhibited an overall reduction in cytokine secretion after an initial amplified immune response. We demonstrate that reduced synapse density observed in the AD organoids is prevented with microglial depletion. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins. In this study, we used microglia-containing AD organoids to quantitatively characterize an evolving immune milieu, made up of a diverse of collection of activation patterns and immune responses, to identify how a dynamic, overall neuroinflammatory state negatively impacts neuronal health and the cell-specific contribution of microglia.

Dataset Information

APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

Publications

<i>APOE3</i> Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

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