Mini P. Sajan, Michael Leitges, Colin Park, David M. Diamond, Jin Wu, Barbara C. Hansen, Mildred A. Duncan, Christopher A. Apostolatos, Andre H. Apostolatos, Mark Kindy and Robert V. Farese* Pages 941 - 955 ( 15 )
<P>Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer’s disease. <P> 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 Aβ<sub>1-40/42</sub> 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. <P> 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. <P> 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.
BACE1, atypical PKC, PKC-lambda/iota, brain, liver, A-beta, Alzheimer’s disease, dementia, type 2 diabetes mellitus.
Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, FL, Division of BioMedical Sciences, Faculty of Medicine; Memorial University of Newfoundland, St. John`s, Newfoundland, CanadaA1B 3V64Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, FL, Departments of Psychology and Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida, FL, Departments of Psychology and Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida, FL, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tampa , Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, FL, Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, Florida, FL, Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, Florida, FL, Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, Florida, FL, Research Service, James A. Haley Veterans Medical Center, Tampa, Florida, FL, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, FL