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

Abstract

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.

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

“…In addition, the ability of DCA to modulate oxidative stress, inflammation, and mitochondrial dynamics may also contribute to the reduction of Aβ production, as these factors have all been found to be associated with BACE1. 132–134 In conclusion, the current evidence suggests that DCA may have a therapeutic effect on AD, but the pathogenesis of AD is affected by many factors, and further experiments are needed to prove the effects and mechanisms of DCA on AD. 135 , 136 …”

“…In addition, the ability of DCA to modulate oxidative stress, inflammation, and mitochondrial dynamics may also contribute to the reduction of Aβ production, as these factors have all been found to be associated with BACE1. [132][133][134] In conclusion, the current evidence suggests that DCA may have a therapeutic effect on AD, but the pathogenesis of AD is affected by many factors, and further experiments are needed to prove the effects and mechanisms of DCA on AD. 135,136 Huntington's Disease and Parkinson's Disease Huntington's disease (HD) and Parkinson's disease (PD) are also neurodegenerative diseases, and mitochondrial dysfunction is an important factor in the pathogenesis of both diseases.…”