Title : ECRG4 is a potential initiator of amyloid pathology in Alzheimer’s disease and a novel diagnostic plasma marker for the disease
Abstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis underscores the centrality of Aβ accumulation, the precise initiators of this process remain unclear. We hypothesized that Esophageal Cancer-Related Gene 4 (ECRG4), which is associated with cognitive impairment and is upregulated in AD, directly contributes to amyloid pathology. Here, we demonstrated that ECRG4 interacts with amyloid precursor protein (APP)/Aβ, leading to increased APP/Aβ accumulation. We showed that intracerebral injection of synthetic ECRG4 into AD-model mice significantly augmented APP/Aβ deposition. Notably, the co-localization of ECRG4 with APP/Aβ increased with AD severity in human hippocampal tissues.
Furthermore, the observation of ECRG4 accumulation in the blood vessels in AD hippocampus led us to develop a novel ECRG4 ELISA system. We observed that ECRG4 peptides, particularly those consisting of amino acids (AA) 108–132, were elevated in the plasma of approximately 25% of patients with mild cognitive impairment and 50% of those with AD, compared to individuals without dementia. We showed that ECRG4 AA 71-107 killed oligodendrocytes and induced the accumulation of its precursor cells on blood vessels, resulting in the disruption of blood-brain barrier in the early phase of AD progression. Together, our findings reveal that ECRG4 acts as a potential initiator of amyloid pathology in AD and as a novel plasma marker for AD linked to ECRG4-dependent dysfunction in oligodendrocytes.
