Control of β-Site Amyloid Precursor Protein-Cleaving Enzyme-1 Expression by Protein Kinase C-λ/ι and Nuclear Factor κ-B

Background: beta-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of A beta-peptides that form A beta-plaque in Alzheimer's disease. Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of A beta-peptides and phospho-thr-231-tauin the brain; moreover, these effects are blocked by PKC-lambda/iota inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-lambda/iota requirements. We found that total-body heterozygous PKC-lambda knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-lambda activity and production of A beta(1-40/42) and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-lambda haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia. Results: On the other hand, heterozygous knockout of PKC-lambda markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NF kappa B), which is activated by PKC-lambda and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NF kappa B activity and BACE1 levels, and these effects were blocked by various PKC-lambda/iota inhibitors. Conclusion: PKC-lambda/iota controls NF kappa B activity and BACE1 expression; PKC-lambda/iota inhibitors may be used nasally to target brain PKC-lambda/iota or systemically to block both liver and brain PKC-lambda/iota, to regulate NF kappa B-dependent BACE1 and proinflammatory cytokine expression.