Atp11b, a P4-ATPase, is involved in preferentially translocating phosphatidylserine of the cell membrane. It participates in various biological processes, and its abnormal expression is associated with multiple diseases [5]. It may be related to signal transduction in neurons, lipid metabolism, and has implications in cancer metastasis and drug resistance [1,2,3,6]. Genetic models like knockout mice can be used to study its functions.

In Atp11b-knockout mice, there are multiple significant findings. Atp11b deficiency leads to abnormal neural and dendritic morphology in the hippocampus, impairs synaptic plasticity through the MAPK14 signaling pathway [1]. It also causes excessive fatty acid uptake, abnormal neutral lipid synthesis, and mitochondrial energy metabolism in microglia, resulting in the accumulation of pathological lipid droplets in microglia and AD mice. Conversely, overexpression of Atp11b alleviates AD-related symptoms [2]. Atp11b-knockout mice show a shift in gut microbiota abundance, with an increase in pro-inflammatory bacteria and a decrease in probiotics, leading to enhanced oxidative stress, reduced hippocampal cells, aggravated aging-related pathological features, and aging-associated behavior [4]. In breast cancer, low expression of Atp11b promotes metastasis through increased non-apoptotic phosphatidylserine on the cell membrane [3].

In conclusion, Atp11b plays essential roles in neural synaptic plasticity, microglial lipid metabolism, and may impact breast cancer metastasis and Alzheimer's disease pathology. The use of Atp11b knockout mouse models has significantly advanced our understanding of its functions in these disease-related biological processes, providing potential therapeutic targets for these conditions.

References:

1. Wang, Jiao, Li, Weihao, Zhou, Fangfang, Xie, Jiang, Wen, Tieqiao. . ATP11B deficiency leads to impairment of hippocampal synaptic plasticity. In Journal of molecular cell biology, 11, 688-702. doi:10.1093/jmcb/mjz042. https://pubmed.ncbi.nlm.nih.gov/31152587/

2. Zhang, Yuchen, Zhang, Shibo, Zhao, Xuyu, Zhao, Robert Chunhua, Wang, Jiao. 2025. ATP11B Modulates Microglial Lipid Metabolism and Alleviates Alzheimer's Disease Pathology. In MedComm, 6, e70139. doi:10.1002/mco2.70139. https://pubmed.ncbi.nlm.nih.gov/40123832/

3. Xu, Jun, Su, Sek Man, Zhang, Xin, Deng, Chu-Xia, Xu, Xiaoling. . ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine. In The Journal of clinical investigation, 132, . doi:10.1172/JCI149473. https://pubmed.ncbi.nlm.nih.gov/35025764/

4. Liu, Cuiping, Zhang, Shibo, Shi, Hongwei, Ward, Natalie, Wang, Jiao. 2022. Atp11b Deletion Affects the Gut Microbiota and Accelerates Brain Aging in Mice. In Brain sciences, 12, . doi:10.3390/brainsci12060709. https://pubmed.ncbi.nlm.nih.gov/35741595/

5. Wang, Jiao, Wang, Qian, Zhou, Fangfang, Wang, Dong, Wen, Tieqiao. . Silencing of ATP11B by RNAi-Induced Changes in Neural Stem Cell Morphology. In Methods in molecular biology (Clifton, N.J.), 1622, 51-61. doi:10.1007/978-1-4939-7108-4_4. https://pubmed.ncbi.nlm.nih.gov/28674800/

6. Tang, Tianyu, Huang, Xing, Zhang, Gang, Zhi, Xiao, Liang, Tingbo. . Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis. In Journal for immunotherapy of cancer, 10, . doi:10.1136/jitc-2021-004129. https://pubmed.ncbi.nlm.nih.gov/35288467/