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

Curr Alzheimer Res. 2021;18(12):941-955. doi: 10.2174/1567205019666211222120448.

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.

Keywords: A-beta; Alzheimer’s disease; BACE1; PKC-lambda/iota; atypical PKC; brain; dementia; liver; type 2 diabetes mellitus..

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid Precursor Protein Secretases* / genetics
  • Amyloid Precursor Protein Secretases* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases* / genetics
  • Aspartic Acid Endopeptidases* / metabolism
  • Diabetes Mellitus, Experimental*
  • Mice
  • NF-kappa B* / metabolism
  • Protein Kinase C* / genetics

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • NF-kappa B
  • Protein Kinase C
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse