Figure 6

Hypoxia contributes to Aβ deposition by activating BACE1 transcription. Hypoxia activates BACE1 by three distinct mechanisms: generation of oxidative stress and the subsequent activation of the JNK pathway; activation of HIF-1 transcription factor which activates BACE1 promoter directly or indirectly through the activation of NF-κB and RAGE; activation of calpain and cdk5 resulting from increased calcium concentrations. By activating BACE1 transcription, hypoxia thus leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.