A novel arctigenin derivative ameliorates memory impairment and pathologies by activating adiponectin receptor 1-mediated autophagy and regulating amyloid precursor protein processing of Alzheimer's disease

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative condition marked by neurotic plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) in the brain's medial temporal lobe and neocortical structures. It is reported that arctigenin (ATG) has the effect to reduce the expression of the enzyme 1 that cleaves β-site amyloid precursor protein and increase Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression in Alzheimer's mice by promoting autophagy. 3-month-old 5×FAD mice were orally treated with drug for 3 consecutive months. Water maze and new object recognition were used to assess cognitive impairment in 5xFAD mice. In the hippocampus of the mouse brain, APP processing-related proteins (sAPP _β , BACE1) and autophagy (LC3B, P62, LAMP1) related proteins were detected. Some experiments related to animal data were conducted on N2a/APPswe cells to further identify the effect and mechanisms of drug. ARC-18 improved behavioral performance in water maze and new object recognition in 5xFAD mice. ARC-18 alleviated the over-aggregation of Aβ in the hippocampus and cortex of 5xFAD mice. ARC-18 promotes autophagy and inhibits amyloidogenic processing of APP in 5xFAD mice and N2a/APPswe cells. ARC-18 improves AD-like pathologies and memory impairment by increased clearance of Aβ by activating adiponectin receptor 1-mediated autophagy and reduced Abeta production via regulating amyloid precursor protein (APP) processing.