## 5 Therapeutic Implications of WA in AD
### Role of WA and Its Derivatives
#### 5.1.4 WA Blocks the Neuroinflammation in AD
In this respect, two main groups of inflammasomes have been recognized based on the presence of their intracellular receptors, AIM2-like receptor inflammosomes (ALR) and Nod-like receptor inflammosomes (NLR) [174]. Numerous studies using inflammatory disease models showed that WA interferes with the development of a crucial subtype of the NLR class inflammam-some NLRP3 (Figure 3). Stimulation of the NLRP3 inflammasome is induced by protein aggregations such as \(\beta\)-amyloids, toxins, pathogens, and crystals [175; 176; 177]. Abnormal activation of NLRP3 has been known to be involved in the initiation and progression of inflammation [178]. Though the precise biological mechanism of WA-mediated blocking of NLRP3 inflammasome development needs further exploration, medicinal use of WA may provide a chance to control cytokine activation in inflammatory diseases [177]. It is essential to know that the impact of WA on other inflammasome subtypes also needs to be examined, since some studies have shown that WA treatment increases the expression and initiation of AIM2 inflammosomes of M2 macrophages, resulting in a pro-inflammatory instead of the anti-inflammatory response in immune cells [20; 179]. WA Regulates Heat Shock Proteins  
WA may control the activity of heat shock proteins (HSPs) that are highly conserved molecular chaperones associated with the transporting, folding, maintenance, and assembly of main regulatory protein kinases [180; 181]. In addition, WA controls the target proteins of HSP90 such as AKT and IKKK-complex by attacking and disassociating the CDC37-HSP90 complex, by either preventing the protein cleavage of CDC37 [182] or by straight binding of HSP90 itself. The therapeutic significance of WA in CDC37-HSP90 blockage has already been proven in N9 microglial cells, where one specific target of HSP90 kinase is significantly reduced [182]. On the other hand, LRRK2 is a multi-domain unidentified protein often mutated in patients with sporadic and familial AD. Most mutations in this protein kinase are linked to functional activities such as enhanced protein expression, which is essential for the etiology of inflammatory diseases [20]. Interestingly, a more helpful anti-inflammatory function of WA was proven in TAR-DNA binding protein transgenic mice (TDP43) [183]. Altogether, these data verify that WA has tremendous potential as a natural neurotherapeutic agent for improving cognitive deficits associated with AD. Thus, its application in other neurodegenerative disease models needs to be investigated [21]. Figure 3: Overview of inflammatory signaling pathways altered by WA through direct molecular targets. Fibrillary A\(\beta\), oxidative stress, DAMP, and PAMP can contribute to the activation of the inflammasome. A\(\beta\) fibrils trigger the activation of microglial cells and thus give signal 1 via NF-kB transcription of pro IL-1\(\beta\) and NLRP3. Intracellular aggregation of soluble A\(\beta\) and lysosomal rupture by phagocytosis A\(\beta\) fibrils may perform another signal, and oxidative stress contributes to the formation of an active NLRP3 inflammasome. Active caspase-1, released from active NLRP3, converts IL-1\(\beta\) pro to active IL-1\(\beta\), which is released into extracellular space and leads to neuroinflammation and finally AD. WA prevents NLRP3 inflammasome formation and activation by blocking several steps of this pathway. Abbreviations: ROS: reactive oxygen species; NLEP3: NOD-like receptor protein 3; DAMP: damage-associated molecular pattern; PAMP: pathogen-associated molecular pattern; COX-2: cyclooxygenase-2; IxB: inhibitory subunit of NF-kB; IL-18: interleukin-18; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1; AD: Alzheimer disease; WA: uithaferin A.