Plasma ECRG4 as a novel diagnostic marker for Alzheimer's disease associated with oligodendrocyte dysfunction

Current treatments for Alzheimer's disease (AD) primarily focus on slowing disease progression, emphasizing the urgent need for a reliable diagnostic method for early-stage Alzheimer's (EAD). Our investigation, which is based on the finding that the secretory protein Esophageal Cancer Related Gene 4 (ECRG4) is elevated in the hippocampus of AD patients, led to the creation of a novel ELISA system for ECRG4 detection. We observed that ECRG4 peptides, particularly the fragment spanning amino acids 108-132, were elevated in the plasma of approximately 25% of patients with mild cognitive impairment (MCI) and 50% of those with AD, compared to individuals without dementia. RNA sequencing of plasma samples revealed decreased levels of carbohydrate sulfotransferase 3 (CHST3) mRNA, which is mainly expressed in oligodendrocyte (OLG)-lineage cells, in ECRG4-positive patients. Functional analyses demonstrated that the ECRG4 (71-107) peptide induced cytotoxicity in oligodendrocytes in vitro and reduced the expression of the OLG marker galactocerebroside in the corpus callosum following intracerebral injection. Additionally, peptide injection resulted in extravascular IgG leakage and the accumulation of OLG precursor cells (OPCs), which are crucial for myelin regeneration, around the blood vessels. These phenomena were similarly observed in the hippocampi of patients with EAD. Collectively, these findings establish ECRG4 as a novel serum marker for AD and suggest its association with ECRG4-dependent OLG dysfunction.