ICA1 affects APP processing through the PICK1‐PKCα signaling pathway

• Published in: CNS neuroscience & therapeutics 2024-06, Vol.30 (6), p.e14754-n/a
• Main Authors: Ji, Liangye, Meng, ZiJun, Dong, Xiangjun, Wang, Qunxian, Jiang, Yanshuang, Zhang, Jie, Hu, Dongjie, Guo, Shipeng, Zhou, Weihui, Song, Weihong
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino acids; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Antibodies; Antigens; APP; Autoimmune diseases; Brain; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins; Cells; Endoplasmic reticulum; Female; Humans; ICA1; ICA1 protein; Kinases; Male; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurodegenerative diseases; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; Phosphorylation; PICK1; PKCα; Plasmids; Protein kinase C; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Proteins; Sequence analysis; Signal processing; Signal transduction; Signal Transduction - physiology; Synaptic plasticity; Transcriptomes
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/cns.14754

Aims Islet cell autoantigen 1 (ICA1) is involved in autoimmune diseases and may affect synaptic plasticity as a neurotransmitter. Databases related to Alzheimer's disease (AD) have shown decreased ICA1 expression in patients with AD. However, the role of ICA1 in AD remains unclear. Here, we report that ICA1 expression is decreased in the brains of patients with AD and an AD mouse model. Results The ICA1 increased the expression of amyloid precursor protein (APP), disintegrin and metalloprotease 10 (ADAM10), and disintegrin and metalloprotease 17 (ADAM17), but did not affect protein half‐life or mRNA levels. Transcriptome sequencing analysis showed that ICA1 regulates the G protein‐coupled receptor signaling pathway. The overexpression of ICA1 increased PKCα protein levels and phosphorylation. Conclusion Our results demonstrated that ICA1 shifts APP processing to non‐amyloid pathways by regulating the PICK1‐PKCα signaling pathway. Thus, this study suggests that ICA1 is a novel target for the treatment of AD. In this study, we demonstrated that ICA1 alters APP processing and shifts it to non‐amyloid pathways by regulating the PICK1‐PKCα signaling pathway, and we suggested ICA1 as a potential therapeutic target for AD therapy by modulating APP processing.