A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Cellular and Molecular Neuroscience
Ting, L. L., Lu, H. T., Yen, S. F., Ngo, T. H., Tu, F. Y., Tsai, I. S., Tsai, Y. H., Chang, F. Y., Li, X. J., Li, S., Lee, C. K., Kao, S. H., Kuo, Y. M., & Lin, Y. F. (2019). Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells. Molecular Neurobiology, 56(11), 7572-7582. https://doi.org/10.1007/s12035-019-1587-1