Akt and CHIP coregulate tau degradation through coordinated interactions.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by tau protein aggregation.
• Cytosolic chaperones may fail to clear phosphorylated tau, leading to toxic intermediates.
• The cellular kinase Akt's role in tau clearance is investigated.

Purpose of the Study:

• To elucidate the mechanism of tau clearance involving the Akt kinase.
• To understand how Akt interacts with tau, CHIP, and Hsp90.
• To investigate Akt's influence on tau phosphorylation and its implications for AD.

Main Methods:

• Investigated Akt ubiquitination and degradation via the CHIP/Hsp90 complex.
• Assessed Akt's regulation of CHIP-induced tau ubiquitination and degradation.
• Examined the interaction between Akt and PAR1/MARK2 and its effect on tau phosphorylation.
• Analyzed tau phosphorylation sites in Akt1 knockout mice.

Main Results:

• Akt degradation by CHIP/Hsp90 is crucial for tau clearance.
• Akt inhibits CHIP-mediated tau ubiquitination and degradation.
• Akt enhances PAR1/MARK2 activity, promoting tau hyperphosphorylation at specific sites.
• Akt1 knockout mice show reduced tau phosphorylation at PAR1/MARK2 sites.

Conclusions:

• Akt is a key regulator of tau biology, influencing both kinase and protein quality control pathways.
• Dysfunctional Akt-mediated regulation of tau may contribute to Alzheimer's disease pathology.
• Akt's role provides a link between tau homeostasis and common AD-related pathway disruptions.