Figure 1.

HMGB1/RAGE and HMGB1/TLR4 signaling pathways in AD: HMGB1 can interact with extracellular Aβ peptides and decrease Aβ deposition by inhibiting Aβ clearance by microglia, as well as increasing β- and γ-secretase activity. RAGE enhances production of Aβ, abnormal Tau hyperphosphorylation, and NFTs formation. HMGB1/RAGE and HMGB1/TLR4 signaling induce neuroinflammation by activating the NF-κB pathway, increasing production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β, activating microglia and astrocytes in a reactive and inflammatory state, and thus aggravating the AD pathogenesis through a vicious cycle of inflammation and oxidative damage. RAGE/CaMKK-β-AMPK, the RAGE/ERK1/2, RAGE/GSK-3β, and RAGE/NF-κB pathways have been involved in the regulation of abnormal Tau hyperphosphorylation and Aβ pathology. RAGE signaling has been also implicated in synaptic dysfunction, reduced AChE activity, and neurodegeneration. However, activation of RAGE/NF-κB pathway by HMGB1 in adult NPCs promotes neuronal differentiation and formation of new neurons, leading to increased adult neurogenesis. In addition, HMGB1 may play dual roles in AD pathogenesis, since it can also contribute to reparative mechanisms in the AD brain. AD, Alzheimer’s disease; HMGB1, High mobility group box 1; RAGE, Receptor for advanced glycation end products; TLR4, Toll-like receptor 4; Aβ, Amyloid beta; NFTs, Neurofibrillary tangles; CaMKK-β,Ca²⁺/calmodulin-dependent protein kinase kinase-β; ERK1/2, Extracellular signal regulated kinase ½; NPCs, Neural progenitor cells; IL, Interleukin; NF-κβ, Nuclear factor κ light chain enhancer of activated β cells; TNF-α, Tumor necrosis factor-α.