# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 1 Introduction  
Tyrosine kinases constitute a large family of enzymes that catalyze the phosphorylation of tyrosine residues on target proteins, serving as pivotal regulators of intracellular signaling pathways. Tyrosine kinases can be divided into receptor tyrosine kinases, which promote transmembrane signaling by auto-phosphorating at the cell membrane level responding to extracellular ligands, and non-receptor or cytoplasmic tyrosine kinases, which mediate downstream signaling cascades intracellularly [1]. Tyrosine phosphorylation regulates numerous cellular processes including proliferation, differentiation, migration, survival,and immune responses. Dysregulation of tyrosine kinase activity has been implicated in various pathological conditions such as cancer, immune disorders, and neurodegenerative diseases [1; 2; 3]. Hence, tyrosine kinases have become attractive therapeutic targets, with numerous inhibitors already approved for clinical use in oncology and inflammatory diseases [4; 5]. Among the non-receptor tyrosine kinases, Bruton Tyrosine Kinase (BTK) occupies a critical role in hematopoietic signaling networks [6; 7; 8]. BTK is predominantly expressed in B cells, myeloid cells, and platelets, where it transduces signals from the B-cell receptor (BCR), Fc receptors, and toll-like receptors (TLRs), thereby regulating cellular activation, proliferation, differentiation, and survival [6]. Germline mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency characterized by profound B-cell developmental arrest and consequent antibody deficiency, underscoring BTK's essential role in adaptive immunity [9]. While BTK's canonical functions have been extensively studied in hematopoietic cells, growing evidence has expanded its relevance to neuroimmune interactions, particularly in the context of neurodegenerative diseases. Conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischemic stroke (IS), and Huntington's disease are characterized by progressive loss of neuronal structure and function, leading to cognitive and motor impairments [10]. The common thread across these conditions is neuroinflammation, primarily driven by the activation of resident immune cells in the central nervous system (CNS), especially microglia, and the eventual infiltration of peripheral immune cells. Microglia are the CNS's innate immune sentinels, playing dual roles in neuroprotection and neurotoxicity depending on their activation state [11]. Dysregulated microglial activation contributes to sustained neuroinflammatory responses and the release of pro-inflammatory cytokines, reactive oxygen species (ROS), and other neurotoxic mediators, thereby exacerbating neuronal damage. Recent studies have demonstrated that BTK is expressed in microglia and myeloid-derived cells within the CNS, where it modulates signaling pathways triggered by TLRs and Fc receptors, key receptors involved in innate immune activation [12; 13]. BTK activation in microglia promotes inflammatory signaling cascades including NF-xB and inflammasome pathways, which amplify neuroinflammatory responses [2]. This mechanistic insight has fueled interest in targeting BTK to modulate neuroinflammation in neurodegenerative disorders. Pharmacological BTK inhibitors (BTKis), originally developed for B-cell malignancies such as chronic lymphocytic leukemia and mantle cell lymphoma, exhibit potent immunomodulatory properties but also the ability to cross the blood-brain barrier (BBB), exerting modulatory effects over the CNS-resident immune cells [14]. Preclinical models of neurodegenerative diseases treated with BTKis have shown reductions in microglial activation, decreased production of pro-inflammatory mediators, and attenuation of neurodegeneration, suggesting neuroprotective potential [12; 13].