Akt-activated GSK3β inhibitory peptide effectively blocks tau hyperphosphorylation

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Tau hyperphosphorylation and neurofibrillary tangles correlate with cognitive decline in Alzheimer's disease (AD).
• Glycogen synthase kinase 3β (GSK3β) overexpression contributes to tau hyperphosphorylation, making it a therapeutic target for AD.
• Existing GSK3β inhibitors often cause side effects due to interference with essential GSK3β functions.

Purpose of the Study:

• To develop a novel, targeted GSK3β inhibitor peptide (GIP) activated by Akt.
• To evaluate GIP's efficacy in blocking GSK3β-induced tau hyperphosphorylation in vitro and in vivo.
• To assess GIP's neuroprotective effects and therapeutic potential for Alzheimer's disease.

Main Methods:

• Constructed a novel GSK3β inhibitory peptide (GIP) by combining LRP6's PPPSPxS motif and GSK3β's Akt targeted sequence.
• Tested GIP's ability to inhibit tau phosphorylation in hippocampal homogenates and neuroblastoma cells.
• Administered GIP intravenously to a 3xTg-AD mouse model to assess in vivo efficacy and safety.

Main Results:

• GIP effectively inhibited GSK3β-induced tau phosphorylation in vitro.
• GIP, when cell-permeable, reduced Aβ-induced tau phosphorylation and cell death in neuroblastoma cells.
• In vivo, GIP significantly decreased hippocampal tau phosphorylation in AD mice, improved memory, and showed no adverse effects on Aβ plaques or neuroinflammation.

Conclusions:

• The Akt-activated GIP represents a novel therapeutic strategy for targeting tau hyperphosphorylation in Alzheimer's disease.
• GIP demonstrates neuroprotective effects by reducing tau pathology and ameliorating cognitive deficits.
• This targeted inhibition of GSK3β offers a promising approach for AD drug development with potentially fewer side effects.