Amyloid precursor protein carboxy-terminal fragments as catalyzers of endolysosomal dysfunction in Alzheimer’s disease

Proteolytic processing of the amyloid precursor protein (APP) generates not only the well-known β-amyloid (Aβ) peptides but also APP C-terminal fragments (APP-CTFs). Recent evidence from studies in murine- or human-derived (neuronal) models suggests that APP-CTFs may independently contribute to Alzheimer's disease (AD) pathology by disrupting cellular homeostasis. This review highlights pathological effects unique to APP-CTFs that are independent of Aβ, shedding light on their distinct role in disease progression. We explore the mechanisms underlying APP-CTF-induced toxicity, with a focus on their contribution to endolysosomal dysfunction. APP-CTFs impair lysosomal function and disrupt calcium signaling between the endoplasmic reticulum and lysosomes, compounding organelle dysfunction. Understanding these mechanisms will aid the design of preventive therapeutic strategies that take into account the impact of APP-CTFs on AD pathology.