# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 4 Discussion  
The involvement of BTK in a spectrum of neuroinflammatory pathways has prompted increasing interest in its therapeutic targeting across neurodegenerative diseases [22]. As reviewed here, BTK not only is integral to B-cell development and function but also plays a pivotal role in modulating innate immune responses via microglia and myeloid cells in the CNS. This dual functionality uniquely positions BTK at the crossroads of adaptive and innate immunity, a feature that is particularly relevant in chronic neurodegenerative conditions characterized by both systemic and CNS-compartmentalized inflammation. Several key themes emerge from the current evidence. First, BTK activation amplifies deleterious neuroimmune interactions that contribute to neuronal loss [19]. In microglia, BTK signaling propagates pro-inflammatory pathways including the NF-\(\kappa\)B axis and the NLRP3 inflammasome, which are implicated in the production of cytokines such as IL-19 and TNF-\(\alpha\). These mediators, in turn, exacerbate oxidative stress, synaptic dysfunction, and neuronal death. Second, BTKis, initially developed for hematologic malignancies, exhibit immunomodulatory effects that extend beyond the hematopoietic system. Their ability to penetrate the BBB and selectively modulate pathological immune responses in the CNS without inducing global immunosuppression is a critical therapeutic advantage [14]. The therapeutic rationale for BTK inhibition in neurodegeneration is underscored by the convergence of neuroinflammatory mechanisms across multiple disorders. In AD, BTK appears to mediate microglial phagocytic dysfunction and pro-inflammatory activation in response to amyloid pathology [51]. In PD, BTK amplifies dopaminergic neurotoxicity via TLR and \(\alpha\)-synuclein-triggered pathways [57]. In MS, BTK orchestrates both B-cell-driven autoimmunity and microglial activation, supporting its targeting in both relapsing and progressive forms [24]. In ischemic stroke, the timing and extent of BTK activation shape the extent of secondary injury and inflammation-driven neuronal damage [79]. Finally, inHD, early and sustained microglial activation, potentially BTK-dependent, has emerged as a tractable contributor to disease onset and progression [88]. Preclinical studies across diverse animal models consistently demonstrate, as mentioned above, that BTK inhibition attenuates neuroinflammation, preserves neuronal integrity, and improves behavioral outcomes [29]. Notably, BTKis have been shown to reduce microglial reactivity, limit the production of neurotoxic cytokines, and promote protective phenotypes. These findings support the notion that BTK inhibition not only reduces immune-driven damage but may also foster a reparative environment conducive to neurodegeneration. The clinical pipeline for BTKis in neurodegeneration is rapidly expanding. Several compounds, including evobrutinib and fenebrutinib, are currently being tested for MS. Safety and tolerability data from oncology and autoimmune contexts are encouraging, particularly with respect to long-term administration and immune preservation [91]. Importantly, emerging data suggest that BTKis may synergize with existing therapies, potentially enhancing their therapeutic efficacy and broadening their clinical utility [92; 93]. Nevertheless, several limitations and challenges must be addressed. The pleiotropic functions of BTK across different immune compartments raise concerns regarding off-target effects and unintended immune modulation [14]. Furthermore, the extent of BTK involvement may differ by disease stage and CNS region, requiring precise characterization of the patient subgroups that may benefit most from BTK-targeted therapies. In addition, the pharmacokinetics, CNS penetrance, and selectivity profiles of different BTKis vary substantially, influencing therapeutic windows and clinical outcomes.