Tyrobp, also known as TYRO protein tyrosine kinase-binding protein, DAP12 or KARAP, is a transmembrane adaptor protein. It serves as a receptor-activating subunit in natural killer cells and is expressed in various cell types like monocytes, macrophages, dendritic cells, osteoclasts and microglia. It is a downstream adaptor for several receptors involved in Alzheimer's disease (AD) such as SIRP1β, CD33, CR3, and TREM2, playing a key role in signal transduction across these receptors and thus in brain homeostasis [1,2].

In AD mouse models, constitutively Tyrobp-deficient mice (APP/PSEN1;Tyrobp-/-and MAPTP301S;Tyrobp-/-) showed preserved learning behavior and synaptic electrophysiological function despite robust cerebral amyloidosis or tauopathy. Tyrobp deficiency prevented the accumulation of complement C1q associated with these proteinopathies, suggesting its role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype [1]. In Huntington's disease Q175 mouse model, Tyrobp knockout decreased microglial expression of disease-associated genes, mitigated astrogliosis and motor deterioration, and reduced pro-inflammatory pathways specifically active in human HD brain [4]. In aortic dissection mouse models, global and myeloid cell-specific deficiency of Tyrobp increased the incidence of aortic dissection, exacerbated extracellular matrix degradation and macrophage infiltration, while macrophage depletion mitigated these adverse effects, indicating that the Trem2/Tyrobp axis plays a role in aortic dissection development [3].

In conclusion, Tyrobp is crucial in signal transduction across multiple receptors, especially in microglia. Gene knockout mouse models have revealed its significant role in neurodegenerative diseases like Alzheimer's and Huntington's, as well as in cardiovascular disease such as aortic dissection. These models help to understand the complex biological functions of Tyrobp and its potential as a therapeutic target in these disease areas.

References:

1. Haure-Mirande, Jean-Vianney, Audrain, Mickael, Ehrlich, Michelle E, Gandy, Sam. 2022. Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2. In Molecular neurodegeneration, 17, 55. doi:10.1186/s13024-022-00552-w. https://pubmed.ncbi.nlm.nih.gov/36002854/

2. Ma, Jing, Jiang, Teng, Tan, Lan, Yu, Jin-Tai. 2014. TYROBP in Alzheimer's disease. In Molecular neurobiology, 51, 820-6. doi:10.1007/s12035-014-8811-9. https://pubmed.ncbi.nlm.nih.gov/25052481/

3. Zhang, Zenghui, Wu, Maoxiong, Yao, Lei, Liu, Zhaoyu, Chen, Yangxin. 2024. Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice. In Arteriosclerosis, thrombosis, and vascular biology, 45, 119-135. doi:10.1161/ATVBAHA.124.321429. https://pubmed.ncbi.nlm.nih.gov/39508103/

4. Creus-Muncunill, Jordi, Haure-Mirande, Jean Vianney, Mattei, Daniele, Ellerby, Lisa M, Ehrlich, Michelle E. 2024. TYROBP/DAP12 knockout in Huntington's disease Q175 mice cell-autonomously decreases microglial expression of disease-associated genes and non-cell-autonomously mitigates astrogliosis and motor deterioration. In Journal of neuroinflammation, 21, 66. doi:10.1186/s12974-024-03052-4. https://pubmed.ncbi.nlm.nih.gov/38459557/