PPP2R5C Identified as Potential Early Biomarker for Alzheimer's Disease

A recent study published in Cell Reports Medicine identified protein phosphatase 2 regulatory subunit B'β (PPP2R5C) as a potential early biomarker for Alzheimer's disease (AD).

Alzheimer's Disease and Biomarker Need

Alzheimer's disease is a common form of dementia where pathological changes can precede symptom onset by decades. Early and reliable biomarkers are crucial for timely interventions. Current diagnostic methods, such as PET imaging and cerebrospinal fluid (CSF) analysis, are often expensive and invasive.

A key feature of AD pathology is tau protein hyperphosphorylation, which leads to neurofibrillary tangles (NFTs) and neuronal dysfunction. Regulators of tau phosphorylation are considered potential diagnostic biomarker candidates.

Protein phosphatase 2A (PP2A) accounts for approximately 70% of brain tau phosphatase activity. PPP2R5C, highly expressed in the brain, has been linked to AD risk through a single-nucleotide polymorphism.

Research Findings

Identification in Neuron-Derived Exosomes

Researchers investigated PPP2R5C levels in neuron-derived exosomes (NDEs) from plasma. In a discovery cohort, a PPP2R5C-specific peptide progressively decreased from presymptomatic familial AD (pre-FAD) to familial AD (FAD) patients compared to cognitively normal (CN) individuals.

This observation was validated in a second cohort, including CN controls, sporadic AD patients, and individuals with amnestic mild cognitive impairment (aMCI). This suggests that reduced PPP2R5C expression may be associated with early AD pathological processes.

Plasma PPP2R5C as a Biomarker

Given the technical challenges of NDE isolation, researchers assessed total plasma PPP2R5C. In a third cohort, plasma PPP2R5C levels were significantly lower in AD patients compared to CN controls.

Further analysis showed that plasma PPP2R5C levels were approximately 61.3% lower in aMCI and 31.6% lower in AD than in CN controls.

Plasma PPP2R5C distinguished AD from CN controls with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.8494. It also differentiated aMCI from controls with an AUROC of 0.7360.

Plasma PPP2R5C positively correlated with Mini-Mental State Examination (MMSE) scores and negatively with plasma phosphorylated tau levels (p-tau181, p-tau217, p-tau231), supporting its relevance to tau pathology.

Brain Expression and Early Stages

Postmortem brain analyses revealed lower PPP2R5C levels in aged AD patients compared to young and aged CN individuals. Immunohistochemical staining of Braak-graded AD brain samples indicated PPP2R5C expression decreased as early as Braak stage II, preceding extensive tau pathology.

Mechanistic Role

Experiments showed PPP2R5C interacts with tau, reduces phosphorylated tau and total tau levels, and enhances PP2A enzymatic activity. Silencing PPP2R5C decreased PP2A activity.

PPP2R5C-driven tau degradation was blocked by autophagy-lysosome inhibitors, implicating the autophagolysosomal pathway. A negative correlation was observed between PPP2R5C expression and phosphorylated ULK1, and molecular docking suggested an interaction between PPP2R5C and ULK1.

Clinical Implications

These findings suggest PPP2R5C may serve as a plasma biomarker candidate associated with early AD pathological processes, potentially preceding tau hyperphosphorylation.

However, the study does not establish PPP2R5C as a definitive diagnostic marker. Larger, longitudinal, and ethnically diverse cohort studies, along with assay standardization, are required for clinical implementation in AD diagnosis.