Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) andprotein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-oldmice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-oldmice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, inmice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.