TYROBP (also known as DAP12) is a transmembrane adaptor protein that plays a critical role in immune cell signaling and activation. TYROBP non-covalently associates with various activating receptors on immune cells, including natural killer cells, macrophages, microglia, and dendritic cells, to mediate cellular activation through tyrosine phosphorylation of its immunoreceptor tyrosine-based activation motif (ITAM) domain 1. In the brain, TYROBP serves as the downstream adaptor for several receptors implicated in Alzheimer's disease, including TREM2, SIRP1β, CD33, and CR3, and is significantly upregulated in AD patients 23. The protein enhances microglial phagocytic activity for amyloid-β clearance and apoptotic neuron removal while suppressing inflammatory responses 2. Remarkably, TYROBP deficiency in mouse models provides genetic resilience against both cerebral amyloidosis and tauopathy, preserving learning behavior and synaptic function by preventing complement C1q accumulation 1. TYROBP also plays protective roles in cardiovascular disease, as Trem2/Tyrobp signaling protects against aortic dissection by inhibiting macrophage activation 4. In human disease, homozygous inactivating variants cause Nasu-Hakola disease, an early-onset dementia characterized by dysregulated microglia with heightened wound healing pathways 5.