Βackground:
β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the
production of Aβ-peptides that form Aβ-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 Aβ-peptides and phospho-
-thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as
chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to
further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development
of glucose intolerance and hyperinsulinemia.
Results:
On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of
BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B
(NFκB), which is activated by PKC-λ 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
NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors.
Conclusion:
PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be
used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.