Investigation of YS620 in regulating beta-amyloid homeostasis via autophagy in Alzheimer's disease

Abstract

Alzheimer’s Disease is an age-related, gradually progressive neurodegenerative disorder. It is featured with behaviour changes, language difficulties and cognitive impairments, and has two abnormal structures presenting in the patient’s brain as hallmarks, the neurofibrillary tangles (NFTs) and beta amyloid (Aβ) plaques. Aβ plaques are formed by Aβ peptides which can be generated from amyloid precursor protein (APP) through β-secretase and γ-secretase cleavages. Aβ peptides operate as a major toxic species in AD and trigger a series of AD pathological events including tauopathy, facilitating the formation of NFTs. The autophagy-lysosomal pathway is one of the major intracellular protein degradation systems. It is a multi-step mechanism including autophore nucleation, autophagosome maturation, autophagosome- lysosome fusion and lysosomal degradation. Dysregulation of autophagy contributes to neuronal cell death in AD. Recent studies illustrated that by inducing autophagy, Aβ peptides can be recruited to autophagic vacuoles (AVs) and subjected to lysosomes for further degradation and recycling through the autophagy-lysosomal pathway. Therefore, autophagy may be the potential target for developing novel therapeutical agents to treat AD. In this study, a recently synthesized small molecular compound YS620 was identified as an autophagy inducer in N2a cells and N2aAPPswe cells. Despite the inability to regulate mammalian target of rapamycin (MTOR) or lysosomal-associated membrane protein 1 (LAMP1) in N2a cells, it was demonstrated that autophagy flux was increased by YS620 in an autophagy-related protein 5 (Atg5)- dependent manner. Based on the current understanding that increasing of autophagy may induce the Aβ clearance in vitro. The level of secreted Aβ peptides was detected via ELISA assay in N2aAPPswe cells after YS620 treatment. It was found that YS620 reduced the level of Aβ42 and Aβ42/40 ratio, but not Aβ40 in N2aAPPswe cells. The effect of YS620 was further verified using an in vivo transgenic (Tg) animal model of AD, TgCRND8 mice. After daily treatment with YS620 from 8-weeks to the age of 5months or 8 months, the learning and memory impairment of Tg mice was improved comparing to non-treatment and saline-treated Tg mice, as measured by Morris Water Maze. The compound-treated Tg mice also exhibited a reduction in hippocampal amyloid burden at the age of 8 months comparing to the non-treated Tg mice. Taken together, these results illustrated that YS620 prevented cognitive malfunction in a Tg mouse model of AD with the involvement of autophagy-mediated Aβ clearance. It may be a potentially effective therapeutic compound for AD treatment.