Researchers report that reduced levels of PPP2R5C in the blood may be a sign of early Alzheimer’s disease, providing new insights into tau regulation and future diagnostic strategies.

Study: Neuronal PPP2R5C in plasma may have potential biomarker For early diagnosis of Alzheimer’s disease

In a recent study published in the journal cell report medicineresearchers identified the protein phosphatase 2 regulatory subunit B’β (PPP2R5C) as a potential early biomarker associated with Alzheimer’s disease (advertisement).

Alzheimer’s disease pathology and the need for early biomarkers

AD is the most common form of dementia and disproportionately affects the aging population. Pathological changes in Alzheimer’s disease begin decades before the onset of symptoms, highlighting the importance of identifying reliable early biomarkers to enable disease-modifying interventions at the preclinical stage. Positron emission tomography (pet) Image processing and cerebrospinal fluid (CSF) analysis is expensive and invasive, limiting widespread clinical implementation.

A central feature of Alzheimer’s disease is hyperphosphorylation of the tau protein, which disrupts microtubule stability and promotes the formation of neurofibrillary tangles (NFT), ultimately leading to neuronal dysfunction and cell death. Because tau phosphorylation plays an important role in the progression of Alzheimer’s disease, modulators of tau phosphorylation may serve as potential diagnostic biomarkers.

Protein phosphatase 2A (PP2A) accounts for approximately 70% of the total tau phosphatase activity in the human brain. PP2A is a heterotrimeric complex consisting of a scaffold and a catalytic subunit associated with a variable regulatory subunit. PPP2R5C is highly expressed in the brain, and previous studies have shown that single nucleotide polymorphism (SNP) Influence of the PPP2R5C gene on AD risk. Whether PPP2R5C itself functions as a diagnostic biomarker remained unknown prior to this study.

Proteomic identification of PPP2R5C in neuron-derived exosomes

Researchers investigated PPP2R5C levels in exosomes derived from neurons (near death experience) isolated from plasma samples. The discovery cohort included four cognitively normal individuals (CN) individuals, 4 presymptomatic familial AD (Before the epidemic) participants, and 5 familial AD (fashion) patient. Label-free proteomic analysis showed that PPP2R5C-specific peptides gradually decreased from presymptomatic FAD to FAD compared to cognitively normal controls.

This observation was validated in a second cohort consisting of 32 CN controls, 20 sporadic AD patients, and 12 individuals with amnestic mild cognitive impairment (aMCI) using targeted near-death experience analysis. Findings suggested that reduced PPP2R5C expression may be associated with early AD pathological processes.

Plasma PPP2R5C as a minimally invasive biomarker

Because it is technically difficult to isolate NDEs from plasma, the researchers evaluated total plasma PPP2R5C as a more practical biomarker candidate. In a third cohort of 15 FAD patients and 15 CN controls, plasma PPP2R5C levels were significantly lower in AD patients.

Further analysis showed that plasma PPP2R5C levels were approximately 61.3% lower in aMCI and approximately 31.6% lower in AD compared to CN controls. The AD group showed 52.1% lower plasma PPP2R5C than the aMCI group.

The plasma PPP2R5C has a receiver operating characteristic curve (Orlock) 0.8494, and the AUROC was 0.7360 to distinguish between controls and aMCI. Differentiation between aMCI and AD yielded an AUROC of 0.5931, indicating limited stage discrimination ability.

Plasma PPP2R5C is a mini-mental status test (MMSE) score and plasma phosphorylated tau 181 (p-tau181), p-tau217, and p-tau231 levels, supporting the association of tau with pathology.

Brain expression patterns and changes in the early stages of Braak

Postmortem brain analysis revealed lower PPP2R5C levels in older AD patients compared with younger and older CN, suggesting that aging alone does not substantially reduce PPP2R5C expression.

Immunohistochemical staining of Braak-grade AD brain samples showed decreased PPP2R5C expression early in Braak stage II, when NFT was still relatively limited. In Braak stages II and IV, PPP2R5C levels remain consistently low despite increased NFT accumulation, supporting the hypothesis that PPP2R5C reduction may precede extensive tau pathology.

Mechanistic role of PPP2R5C in tau regulation

Co-immunoprecipitation experiments demonstrated the interaction between PPP2R5C and tau. Increased PPP2R5C expression enhanced PP2A enzyme activity while decreasing phosphorylated tau and total tau levels. Silencing PPP2R5C reduced PP2A activity, suggesting a regulatory role rather than a pure correlation.

Pharmacological inhibitor experiments showed that tau degradation by PPP2R5C was inhibited by autophagy lysosomal inhibitors such as chloroquine, leupeptin, and ammonium chloride, but not by the proteasome inhibitor MG132. These findings implicate the autophagolysosomal pathway in PPP2R5C-mediated tau clearance.

Because unc-51-like kinase 1 (ULK1) complex is thought to regulate early autophagy induction, and the researchers evaluated its involvement. Immunoblotting showed a negative correlation between PPP2R5C expression and phosphorylated ULK1. Molecular docking suggested that PPP2R5C binds to an accessible region on ULK1, and coimmunoprecipitation confirmed the interaction, but binding affinity was not directly quantified.

Clinical significance and need for future validation

Taken together, the findings suggest that PPP2R5C may serve as a plasma biomarker candidate related to early AD pathological processes. PPP2R5C reduction appears to precede tau hyperphosphorylation and was not observed in cognitively normal older adults.

Mechanistically, PPP2R5C interacts with tau, modulates PP2A activity, and promotes tau degradation via the ULK1-dependent autophagolysosomal pathway. However, this study did not establish PPP2R5C as a final diagnostic marker.

Larger, longitudinal, and ethnically diverse cohort studies are needed to validate these findings. Assay standardization and reproducibility studies are essential before plasma PPP2R5C can be incorporated into routine clinical screening and early diagnostic workflows for Alzheimer’s disease.