Akt-activated GSK3β inhibitory peptide effectively blocks tau hyperphosphorylation

Arch Pharm Res. 2024 Nov;47(10-11):812-828. doi: 10.1007/s12272-024-01513-1. Epub 2024 Sep 26.

Abstract

Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Glycogen synthase kinase 3β (GSK3β) overexpression has been implicated in tau hyperphosphorylation, and many GSK3β inhibitors have been developed as potential therapeutic candidates for AD. However, the potent GSK3β inhibitors produced are prone to side effects because they can interfere with the basic functions of GSK3β. We previously found that when the phosphorylated PPPSPxS motifs in Wnt coreceptor LRP6 can directly inhibit GSK3β, and thus, we produced a novel GSK3β inhibitory peptide (GIP), specifically activated by Akt, by combining the PPPSPxS motif of LRP6 and the Akt targeted sequence (RxRxxS) of GSK3β. GIP effectively blocked GSK3β-induced tau phosphorylation in hippocampal homogenates and, when fused with a cell-permeable sequence, attenuated Aβ-induced tau phosphorylation in human neuroblastoma cells and inhibited cell death. An in vivo study using a 3 × Tg-AD mouse model revealed that intravenous GIP significantly reduced tau phosphorylation in the hippocampus without affecting Aβ plaque levels or neuroinflammation and ameliorated memory defects. The study provides a novel neuroprotective drug development strategy targeting tau hyperphosphorylation in AD.

Keywords: Akt; Alzheimer’s disease; GSK3β; Tau phosphorylation.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 beta* / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta* / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Peptides / chemistry
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt* / metabolism
  • tau Proteins* / antagonists & inhibitors
  • tau Proteins* / metabolism

Substances

  • tau Proteins
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Peptides
  • Amyloid beta-Peptides
  • Neuroprotective Agents