Speakers - 2026

Title: Identifying the carboxy terminal of ECRG4 as a potential initiator for amyloid pathology in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of β-amyloid (Aβ) plaques. Although several genetic risk factors, including APOEε4, have been suggested to contribute to AD progression, the mechanisms underlying the brain-specific accumulation of Aβ remain incompletely understood, particularly given that amyloid precursor protein (APP) is also expressed in peripheral organs including the kidney. In this study, we identified Esophageal Cancer-related Gene 4 (ECRG4), a secreted protein predominantly expressed in the choroid plexus, as a potential contributor to Aβ pathology in AD.

ECRG4 was initially identified as a tumour suppressor gene; however, recent studies have demonstrated increased ECRG4 expression in aged mice and in the hippocampus of AD patients. Furthermore, aged ECRG4-deficient mice exhibit improved spatial learning ability, suggesting a potential role for ECRG4 in age-related neurological dysfunction. Nevertheless, the involvement of ECRG4 in AD pathogenesis remains largely undefined.

Using postmortem human hippocampal tissues, we observed significantly elevated ECRG4 expression in early AD (EAD) and AD samples compared with controls, independent of APOE genotype. Immunohistochemical analyses further demonstrated colocalization of ECRG4 with amyloid plaques in the AD hippocampus.

To investigate the mechanistic relationship between ECRG4 and Aβ pathology, we examined the effects of ECRG4 and its cleavage fragments in vitro. Because ECRG4 contains predicted furin and thrombin cleavage sites, full-length ECRG4 and its fragments were analysed. Overexpression studies revealed that both full-length ECRG4 and its carboxy-terminal fragment, ECRG4(133–148), promote endogenous APP/Aβ accumulation.

We next investigated whether ECRG4 interacts with APP-derived fragments. Co-immunoprecipitation analyses demonstrated an interaction between ECRG4 and C99, the β-secretase-derived carboxy-terminal fragment of APP. Surprisingly, subsequent analyses suggested that the APP intracellular domain (AICD), rather than the Aβ region, mediates this interaction.

To examine the pathological effects of ECRG4 in vivo, ECRG4(133–148) peptides were intracerebrally injected into APP^{NL-G-F/NL-G-F} mice. ECRG4(133–148) administration significantly increased Aβ plaque burden and GFAP-positive astrocyte density surrounding the injection site.

Further immunohistochemical analyses of postmortem hippocampal tissues demonstrated that ECRG4(133–148) signals increase with disease progression and colocalise with both Aβ plaques and AICD. Notably, the degree of colocalization between ECRG4(133–148) and AICD increased significantly with disease progression, irrespective of APOE genotype.

Collectively, our findings suggest that ECRG4 may contribute to AD-associated Aβ pathology, potentially through interaction with AICD. Because AICD functions as a transcriptional regulator involved in downstream gene expression, including pathways associated with Aβ clearance, aberrant ECRG4–AICD interactions may disrupt Aβ homeostasis and promote plaque accumulation. These findings identify ECRG4 as a potential upstream regulator of AD pathology and a possible therapeutic target for AD intervention.

What will the audience take away from presentation?

• ECRG4 as a potential novel biomarker and upstream regulator of Alzheimer’s disease pathology

           The audience will gain insight into ECRG4 as a previously underexplored factor potentially involved in the initiation and progression of Aβ pathology in Alzheimer’s disease. Our findings suggest that ECRG4 and its cleavage fragment, ECRG4(133–148), may                   serve as potential biomarkers and therapeutic targets for future AD research and intervention strategies.

• A novel molecular mechanism involving ECRG4–AICD interaction
  The presentation will introduce a potential mechanistic link between ECRG4 and APP/Aβ accumulation through interaction with the APP intracellular domain (AICD), a transcriptional regulator. This may provide researchers with new perspectives regarding the regulation of Aβ homeostasis and the molecular pathways underlying AD progression.
• Translational potential for future diagnostic and therapeutic development
  The identification of ECRG4(133–148) in AD pathology may support future development of ECRG4-targeted diagnostic approaches and antibody-based therapeutics. These findings may also contribute to future biomarker discovery studies, including investigations combining neuroimaging technologies and artificial intelligence analysis for improving AD diagnosis.