# Neuronal PPP2R5C in plasma is a potential biomarker for early diagnosis of Alzheimer’s disease

## TL;DR

A protein called PPP2R5C in blood plasma decreases early in Alzheimer’s disease, making it a promising early diagnostic biomarker.

## Contribution

PPP2R5C is identified as a novel early biomarker for Alzheimer’s disease that declines before tau pathology.

## Key findings

- PPP2R5C levels progressively decrease in pre-symptomatic and familial Alzheimer’s patients.
- PPP2R5C reduction occurs before tau hyperphosphorylation in Alzheimer’s brains.
- PPP2R5C modulates tau levels via autophagolysosomal and PP2A pathways.

## Abstract

Early intervention is the most effective strategy to impede the progression of Alzheimer’s disease (AD), depending on the identification of early diagnostic biomarkers. Here, we isolate neuron-derived exosomes (NDEs) from plasma of familial AD (FAD), presymptomatic FAD (pre-FAD), and healthy controls (cognitively normal [CN]), followed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. A specific peptide from protein phosphatase 2 regulatory subunit B'β (PPP2R5C) shows a progressive decrease from CN to pre-FAD and FAD patients. This decline is further validated in plasma NDEs and brain tissue from amnestic mild cognitive impairment (aMCI) and sporadic AD (SAD) patients. Two independent cohorts confirm the early and differential diagnostic value of plasma PPP2R5C. Immunohistochemistry of Tau Braak-staged brains reveals PPP2R5C reduction preceding Tau hyperphosphorylation. Mechanistically, PPP2R5C interacts with Tau, reducing Tau levels and phosphorylation via unc-51-like kinase 1 (ULK1)-dependent autophagolysosomal activation and PP2A regulation. Our findings suggest that plasma PPP2R5C has the potential to serve as an ideal biomarker for the early diagnosis of AD.

•PPP2R5C is an early-declining marker across pre-symptomatic, familial, and sporadic AD•Multi-cohort demonstrates early and differential diagnostic potential of PPP2R5C for AD•PPP2R5C reduction precedes tau hyperphosphorylation•PPP2R5C reduces Tau and p-Tau via ULK1-dependent autophagolysosomal and PP2A activation

PPP2R5C is an early-declining marker across pre-symptomatic, familial, and sporadic AD

Multi-cohort demonstrates early and differential diagnostic potential of PPP2R5C for AD

PPP2R5C reduction precedes tau hyperphosphorylation

PPP2R5C reduces Tau and p-Tau via ULK1-dependent autophagolysosomal and PP2A activation

Luo et al. identify PPP2R5C in plasma as an early biomarker of Alzheimer’s disease that declines prior to tau hyperphosphorylation. PPP2R5C modulates tau homeostasis via PP2A activation and ULK1-dependent autophagolysosomal pathways, enabling early diagnosis and providing mechanistic insight into AD pathogenesis.