DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates neuroinflammation and amyloid-β deposition in Alzheimer's disease

Daily, K. P.; Badr, A.; Eltobgy, M.; Estfanous, S.; Whitham, O.; Tan, M.; Carafice, C.; Krause, K.; McNamara, A.; Hamilton, K.; Houle, S.; Gupta, S.; Gupta, G.; Madhu, S.; Fitzgerald, J.; Saadey, A.; Laster, B.; Yan, P.; Webb, A.; Zhang, X.; Pietrzak, M.; Kokiko-Cochran, O. N.; Ghoneim, H. E.; Amer, A. O.

doi:10.1101/2023.08.30.555526

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bioRxiv · 10.1101/2023.08.30.555526

DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates neuroinflammation and amyloid-β deposition in Alzheimer's disease

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Abstract

Alzheimers Disease (AD) is the 6th leading cause of death in the US. It is established that neuroinflammation contributes to the synaptic loss, neuronal death, and symptomatic decline of AD patients. Accumulating evidence suggests a critical role for microglia, innate immune phagocytes of the brain. For instance, microglia release pro-inflammatory products such as IL-1{beta} which is highly implicated in AD pathobiology. The mechanisms underlying the transition of microglia to proinflammatory promoters of AD remain largely unknown. To address this gap, we performed Reduced Representation Bisulfite Sequencing (RRBS) to profile global DNA methylation changes in human AD brains compared to no disease controls. We identified differential DNA methylation of CASPASE-4 (CASP4), which when expressed, can be involved in generation of IL-1{beta} and is predominantly expressed in immune cells. DNA upstream of the CASP4 transcription start site was hypomethylated in human AD brains, which was correlated with increased expression of CASP4. Furthermore, microglia from a mouse model of AD (5xFAD) express increased levels of CASP4 compared to wild-type (WT) mice. To study the role of CASP4 in AD, we developed a novel mouse model of AD lacking the mouse ortholog of CASP4, CASP11, which is encoded by mouse Caspase-4 (5xFAD/Casp4-/-). The expression of CASP11 was associated with increased accumulation of pathologic protein aggregate amyloid-{beta} (A{beta}) and increased microglial production of IL-1{beta} in 5xFAD mice. Utilizing RNA sequencing, we determined that CASP11 promotes unique transcriptomic phenotypes in 5xFAD mouse brains, including alterations of neuroinflammatory and chemokine signaling pathways. Notably, in vitro, CASP11 promoted generation of IL-1{beta} from macrophages in response to cytosolic A{beta} through cleavage of downstream effector Gasdermin D (G SDMD). We describe a role for CASP11 and GSDMD in the generation of IL-1{beta} in response to A{beta} and the progression of pathologic inflammation in AD. Overall, our results demonstrate that overexpression of CASP4 due to differential methylation in AD microglia contributes to the progression of AD pathobiology, thus identifying CASP4 as a potential target for immunotherapies for the treatment of AD.

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Daily, K. P., Badr, A., Eltobgy, M., Estfanous, S., Whitham, O., Tan, M., Carafice, C., Krause, K., McNamara, A., Hamilton, K., Houle, S., Gupta, S., Gupta, G., Madhu, S., Fitzgerald, J., Saadey, A., Laster, B., Yan, P., Webb, A., Zhang, X., Pietrzak, M., Kokiko-Cochran, O. N., Ghoneim, H. E., Amer, A. O.. 2023-09-01. DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates neuroinflammation and amyloid-β deposition in Alzheimer's disease. https://doi.org/10.1101/2023.08.30.555526

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