Aplp2, or Amyloid β (A4) precursor-like protein 2, belongs to the APP family. It is widely expressed in human cells and is essential for survival as shown by cross-breeding analysis of knockout mice of APP family molecules [1]. Aplp2 is involved in multiple biological pathways, such as TGF-β signaling, NF-κB signaling, and JNK-dependent cell migration [2,3,4]. It also has implications in various physiological and pathological processes like myopia development, nociceptive information processing, and immune response to Mycobacterium tuberculosis infection [3,5,6].

In gene knockout studies, Aplp2 mutant mice showed heightened susceptibility to mycobacterial infection, accompanied by decreased inducible nitric oxide synthase (iNOS) expression and cytokine production, suggesting its role in safeguarding against mycobacterial infections [3]. Aplp2 knockout mice also developed high degrees of hyperopia and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia, identifying it as a key gene in refractive development [6]. In addition, targeted knockdown of Aplp2 in GABAergic interneurons of GAD2-Cre mice evoked pain hypersensitivity through microglia activation, revealing its importance in controlling microglial activity and pain sensitivity [5].

In conclusion, Aplp2 plays essential roles in multiple biological processes, including host defense against mycobacterial infections, refractive development, and pain sensitivity regulation. The gene knockout mouse models have been crucial in revealing these functions, providing insights into the underlying mechanisms and potential therapeutic targets for related diseases such as tuberculosis, myopia, and neuropathic pain.

References:

1. Yanagida, Kanta, Maruyama, Riki, Tagami, Shinji, Okochi, Masayasu, Fukumori, Akio. 2023. APLP2 is predominantly cleaved by β-secretase and γ-secretase in the human brain. In Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, 23, 311-318. doi:10.1111/psyg.12933. https://pubmed.ncbi.nlm.nih.gov/36691315/

2. Tuersuntuoheti, Amannisa, Li, Qinshan, Teng, Yu, Wu, Wei, Song, Wei. 2023. YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction. In Biochimica et biophysica acta. Molecular cell research, 1870, 119548. doi:10.1016/j.bbamcr.2023.119548. https://pubmed.ncbi.nlm.nih.gov/37479189/

3. Chen, Jianxia, Tang, Fen, Li, Haohao, Wang, Peng, Liu, Feng. 2023. Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage. In International immunopharmacology, 124, 111058. doi:10.1016/j.intimp.2023.111058. https://pubmed.ncbi.nlm.nih.gov/37844466/

4. Wang, Xingjun, Guo, Xiaowei, Ma, Yeqing, Li, Wenzhe, Xue, Lei. 2018. APLP2 Modulates JNK-Dependent Cell Migration in Drosophila. In BioMed research international, 2018, 7469714. doi:10.1155/2018/7469714. https://pubmed.ncbi.nlm.nih.gov/30155482/

5. Li, Yu-Zhe, Zhu, Yue-Bin, Ge, An-Na, Bai, Hu-Hu, Wu, Shu-Jin. 2022. Reduced expression of APLP2 in spinal GABAergic inhibitory neurons contributed to nerve injury-induced microglial activation and pain sensitization. In Neuropharmacology, 224, 109334. doi:10.1016/j.neuropharm.2022.109334. https://pubmed.ncbi.nlm.nih.gov/36442651/

6. Tkatchenko, Andrei V, Tkatchenko, Tatiana V, Guggenheim, Jeremy A, Thinakaran, Gopal, Williams, Cathy. 2015. APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. In PLoS genetics, 11, e1005432. doi:10.1371/journal.pgen.1005432. https://pubmed.ncbi.nlm.nih.gov/26313004/