**3.3. Amyloid‐beta peptide (Aβ) works as a DAMP**

Aβ accumulation is thought to be central to the pathogenesis of Alzheimerʹs disease (AD) [12]. Aβ is produced by proteolysis processing of Amyloid precursor protein (APP). A balance between amyloidogenic processing of APP and the removal of soluble Aβ by clearance pathways and enzyme‐mediated degradation maintains Aβ levels. Aβ is now considered to be one of DAMPs, which activate innate immune cells especially microglia. Putative sensors of Aβ are NLRP3, CD36 andRAGE [13‐15]. By using microglial cells or cell line, we have shown that Aβ produce several cytokines including M‐CSF by PI3K/AKT and NFκB pathway, which stimulate microglial proliferation and migration [16]. Further Aβ induces several chemokines (CCL7, CCL2, CCL3, CCL4 and CXCL2) by PI3K/AKT and Erk pathway in the microglia, which induce the migration of microglia or macrophages [17]. Aβ induced sterile inflammation also produced matrix metalloproteinase (MMP3, MMP12 and MMP13), which might degrade damaged tissue further or might work to degrade Aβ to protect against dangerous stimuli [18]. Aβ induced microglial migration may induces cytoskeletal system. We have shown that Aβ binds to IQGAP1 and actin, which are cytoskeletal components, and may stimulate Rho/Rac signaling [19].

### **3.4. D‐galactose (D‐gal) induced thymus degeneration**

D‐gal at high levels induces the production of reactive oxygen species (ROS) and advanced glycation end products (AGEs; [20]) and induces sterile inflammation. We administered 50 mg D‐gal for 60 days to 2 months old mice. We found unorganized distributions of keratin‐5 and keratin‐8 proteins in the thymus of these hosts, which resembled to aged mice [21].
