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iPSC model of human specific neuroinflammation in Alzheimer’s disease
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iPSC model of human specific neuroinflammation in Alzheimer’s disease
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Journal Article
iPSC model of human specific neuroinflammation in Alzheimer’s disease
2025
Overview
Background Alzheimer’s disease (AD) is a human specific neurodegenerative disorder characterized by loss of memory and cognitive functions associated with amyloid beta 1‐42 (Aβ1‐42) plaques and tau fibrils. In the brain, an elevated level of Aβ1‐42 leads to neuronal death, microglia activation and neuroinflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) binds Aβ1‐42 with high affinity. CHRFAM7A, a human restricted fusion gene, incorporates into the α7nAChR pentamer creating a hypomorphic α7/CHRFAM7A nAChR. We examine how the humanized receptor affects Aβ1‐42 induced neuroinflammation. Method To study the effect of Aβ1‐42 on neuronal and immune cells two models were utilized: human isogenic iPSC model that includes medial ganglionic eminence (MGE) progenitors and microglia like cells (MGL) differentiated from CHRFAM7A null, CHRFAM7A nascent and isogenic CHRFAM7A_KI cell lines; and human AD and age matched control macrophages (28 donors). Result Consistent with a hypomorphic receptor, Aβ1‐42 uptake was mitigated in a dose‐dependent manner in CHRFAM7A carriers in both MGE progenitors and MGL as demonstrated by flow cytometry, ELISA, and immunofluorescence. Interestingly, a decreased Aβ1‐42 uptake resulted in significantly elevated innate immune cytokine expression (interleukin 1beta, interleukin 6, and tumor necrosis factor alpha) in CHRFAM7A carriers compared to null. This finding was consistent with release of the α7nAChR‐mediated anti‐inflammatory effect. Additionally, higher NF‐κB activation in CHRFAM7A carriers compared to null was observed in MGL as shown by a prolonged p65 translocation to the nucleus (immunofluorescence) and an increased p65 phosphorylation (immunoblot). Human variance of Aβ1‐42 effect was characterized in primary human macrophages. Similar to the iPSC model, Aβ1‐42 treatment led to an increased cytokine level in CHRFAM7A carriers compared to non‐carriers. Conclusion We found dual effect of CHRFAM7A on Aβ1‐42 associated pathology in AD: it provides protection against toxic concentration of Aβ1‐42 by decreased uptake through the humanized α7/CHRFAM7A nAChR and increases the innate immune response by switching the α7nAChR from an anti‐inflammatory to pro‐inflammatory transducer. Our iPSC model presents an opportunity to elucidate the molecular mechanism of these processes and establish high throughput screens.
