Protein phosphatase 2A dysfunction in Alzheimer's disease

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Protein phosphatase 2A (PP2A) is a key enzyme family in the brain, regulating numerous cellular processes.
• PP2A dysfunction, including altered methylation and subunit activity, is implicated in Alzheimer's disease (AD) pathogenesis.
• Specific PP2A isoforms and their regulatory mechanisms are crucial for maintaining neuronal health.

Purpose of the Study:

• To review the role of the PP2A/Bα holoenzyme and PP2A methylation in AD.
• To highlight the connection between PP2A deregulation and key AD pathologies like tau hyperphosphorylation and amyloidogenesis.
• To discuss the potential of PP2A-centric therapies for AD.

Main Methods:

• Literature review focusing on PP2A function, regulation, and its involvement in AD.
• Analysis of studies linking PP2A alterations to tau pathology, amyloid precursor protein phosphorylation, and synaptic deficits.
• Examination of the impact of one-carbon metabolism on PP2A methylation and AD risk.

Main Results:

• PP2A/Bα holoenzyme directly binds to tau and acts as the primary tau phosphatase; its deregulation correlates with increased tau phosphorylation in AD.
• Impaired PP2A methylation, linked to altered one-carbon metabolism, is associated with increased sporadic AD risk and AD-like pathology in animal models.
• PP2A methylation disruption leads to decreased PP2A/Bα, enhanced tau and amyloid precursor protein phosphorylation, and neuritic defects.

Conclusions:

• PP2A enzyme deregulation significantly impacts key players in AD pathogenesis, including tau and amyloid pathways.
• Disruption of PP2A/Bα-tau interactions contributes to tau deregulation in AD.
• Developing effective PP2A-targeted therapies for AD requires a deeper understanding of specific PP2A enzyme regulation and function.