The Complexity of Sporadic Alzheimer’s Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction

Figure 4

PF-04494700, an inhibitor of RAGE, can ameliorate sporadic AD and promote neuroprotection by blocking RAGE activation in various cell type. Aging-induced oxidative stress leads to the formation of AGEs, which activate RAGE together with Aβ in various cell type. Triggering of RAGE at the BBB leads to TXNIP expression and subsequent inflammation, BBB leakage, and monocytes infiltration. Moreover, RAGE triggering induces a positive feedback loop enhancing RAGE expression, resulting in enhanced transport of Aβ from the blood to the brain. RAGE activation in glial cells promotes proinflammatory gene expression, which enhanced Aβ production inside the brain and neurotoxicity. RAGE triggering in neuronal cells induces oxidative stress and the production of M-CSF, leading to inflammation. Thus, activation of RAGE in different cell types orchestrates the neuroinflammatory processes that ultimately lead to neurodegeneration. Thus, treatments aimed to inhibit chronic RAGE activation will confer a neuroprotective effect by blocking RAGE-mediated neurovascular dysfunction.