# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 2 Bruton Tyrosine Kinase  
BTK is a member of the Tec family of non-receptor tyrosine kinases, playing a pivotal role in signal transduction in various hematopoietic cell types, as previously mentioned. Structurally, BTK comprises five functional domains: a pleckstrin homology (PH) domain, a Tec homology (TH) domain, Src homology 3 (SH3) and SH2 domains, and a catalytic kinase domain (SH1) [16]. Each domain contributes to BTK's localization, interaction with adaptor proteins, and enzymatic activity. For instance, the PH domain enables membrane recruitment through binding to phosphatidylinositol-3,4,5-trisphosphate (PIP3), a process essential for BTK activation upon receptor stimulation [17]. Upon membrane translocation, BTK is phosphorylated at Tyr551 by upstream Src-family kinases, followed by autophosphorylation at Tyr223, a critical step for full catalytic activation [18]. BTK is most prominently expressed in B lymphocytes, where it mediates BCR activation triggering multiple pathways such as PLC\(\gamma\)2-mediated calcium mobilization, PI3K-AKT signaling, and MAPK cascades, leading to B-cell proliferation, differentiation, and survival [19]. In particular, the antigen interaction with BCR causes activation of Src-family kinases, among which Lyn phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) on IgG\(\alpha\)/IgG, leading to recruitment of BTK via its SH2 domain [20; 21]. Membrane-bound BTK is activated through phosphorylation at Tyr551 and proceeds to phosphorylate PLC\(\gamma\)2, a crucial step that leads to intracellular calcium influx and the activation of downstream transcription factors such as NF-\(\kappa\)B, NFAT, and AP-1 [19]. These events drive gene expression programs involved in B-cell activation and antibody production. However, BTK expression is not limited to B cells. As mentioned above, it is also present in myeloid cells including monocytes, macrophages, dendritic cells, and microglia, the resident macrophages of the CNS, where it regulates innate immune responses. In these cells, BTK acts downstream of Fcy receptors and TLRs, mediating activation of NF-\(\kappa\)B and MAPKs, which promote pro-inflammatory gene expression [22]. Upon ligand recognition, these receptors recruit adaptor proteins such as MyD88 and SYK, which in turn activate BTK. BTK then participates in the formation of signalosomes that activate the IKK complex, leading to NF-\(\kappa\)B nuclear translocation and transcription of inflammatory mediators such as tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)) and interleukins (ILs) 1\(\beta\) (IL-1\(\beta\)) and 6 (IL-6) [23; 24]. Additionally, BTK is implicated in NLRP93 inflammasome activation in microglia and macrophages, further linking it to a neuroinflammatory pathology [25]. In particular, BTK signaling promotes the cytoskeletal rearrangements required for phagocytosis, as well as microglial metabolic polarization, favoring glycolysis and pentose phosphate pathway activity, thereby enhancing ROS generation and sustaining the microglial inflammatory phenotype. By standing at the intersection of innate immune signaling and metabolic control, BTK amplifies and maintains microglial activation [26]. The involvement of BTK in these signaling networks suggests that its dysregulation can amplify maladaptive immune responses. Indeed, hyperactive BTK signaling has been associated with heightened inflammatory cytokine production, ROS generation, and microglial priming, all features commonly observed in neurodegenerative diseases [27; 28]. The convergence of BTK signaling with key inflammatory pathways such as NF-\(\kappa\)B, MAPK, and inflammasome activation underscores its role as a central node in neuroimmune signaling. Importantly, these pathways are dysregulated in neurodegenerative diseases, where persistent activation of microglia sustains a chronic pro-inflammatory environment. Thus, targeting BTK may disrupt multiple pathogenic cascades simultaneously, offering a multifaceted approach to neuroinflammatory modulation (Figure 1).