# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 3 Bruton Tyrosine Kinase's Inhibitors in Neurodegenerative Disease
### Alzheimer's Disease  
AD is the most prevalent form of dementia, affecting over 50 million individuals globally [44]. It is characterized by progressive memory impairment, executive dysfunction, and behavioral changes, ultimately culminating in loss of independence and death. Histopathologically, the disease is marked by extracellular deposits of amyloid-\(\beta\) (A\(\beta\)) peptides forming plaques and intracellular aggregates of hyper-phosphorylated tau protein as neurofibrillary tangles [45]. In recent decades, chronic neuroinflammation has emerged as a third critical pillar in the pathogenesis of AD, intricately interacting with amyloid and tau pathologies. Microglia, the brain's resident macrophages, play a central role in neuroinflammatory responses in AD [46]. Upon encountering A\(\beta\) aggregates, microglia become activated and assume a pro-inflammatory phenotype, characterized by increased secretion of pro-inflammatory cytokines (e.g., IL-1\(\beta\), TNF-\(\alpha\)), chemokines, and ROS. Chronic activation contributes to synaptic loss, impaired phagocytic clearance of A\(\beta\), and further recruitment of peripheral immune cells through BBB disruption. Within this context, BTK is increasingly recognized as a central signaling molecule modulating microglial activity. BTK is upregulated in activated microglia in post-mortem AD brains, particularly in proximity to A\(\beta\) plaques [12]. Mechanistically, BTK is involved in TLR and FcR signaling cascades, which are activated upon recognition of damage-associated molecular patterns (DAMPs) such as aggregated A\(\beta\). BTK activation leads to phosphorylation of PLCy2, initiating calcium mobilization, NF-\(\kappa\)B translocation, and inflammasome priming [47]. For instance, PLCy2 acts downstream of AD-related TREM2, TLR4, BTK, and CSF1R, modulating microglial responses. Moreover, PLCy2 variants have been linked to AD, showing that PLCy2 variant M1141K, which is associated with birutinib resistance, greatly increases PLC activity by disrupting its autoinhibitory activity, whereas the AD-protective P522R variant enhances BTK-mediated signaling without affecting PLC basal activity [48]. BTK is also implicated in NLRP9 inflammasome activation, a key driver of IL-1\(\beta\) maturation and release in AD models [49]. Upon priming through TLRs or Fc\(\gamma\) receptors, BTK is activated and translocates to NLRP93-containing complexes, where it phosphorylates NLRP93 on specific tyrosine residues promoting conformational rearrangement and interaction with the adaptor ASC, thereby facilitating inflammasome oligomerization, caspase-1 activation, and subsequent maturation of IL-1\(\beta\) and IL-18. BTK also enhances potassium efflux and mitochondrial ROS production, which are two critical signals for full inflammasome activation [50]. Preclinical studies have demonstrated the efficacy of BTK inhibitors in modulating these inflammatory processes. In APP/PS1 transgenic mice, ibrtinib administration reduced microglial activation, decreased pro-inflammatory cytokine levels, and significantly improved cognitive performance in behavioral tests [51]. These effects were accompanied by lower A\(\beta\) plaque burden, suggesting that BTK inhibition may restore microglial phagocytic function. Importantly, BTK inhibition appears to selectively modulate pathogenic immune pathways without impairing homeostatic microglial functions. [PERSON] and collaborators demonstrated in vitro, using primary rodent microglia, that ibrtutinib reduces pro-inflammatory gene expression while preserving phagocytic capacity and neurotrophic support [12]. These features are critical for long-term safety in chronic diseases like AD. In addition to its role in innate immunity, BTK may influence adaptive immune responses in AD. B cells are found in the meninges and choroid plexus in AD patients, where they may contribute to local inflammation through antigen presentation and antibody production [52].