ARC-18 Alleviates Alzheimer-like Pathology and Cognitive Deficits via AdipoR1-Mediated Activation of Autophagy and Modulation of APP Processing

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases 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 by promoting Autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP_β, BACE1) and autophagy-related proteins (LC3B, p62, LAMP1) were detected. N2a/APPswe cells were used to do experiments to further identify the effect and mechanisms of the drug. Our study demonstrated that ARC-18 enhances the behavioral performance of 5 × FAD mice and mitigates Aβ aggregation in the hippocampus and cortex. This effect is achieved through the activation of Adiponectin Receptor 1 (AdipoR1)-mediated Autophagy and the reduction of Aβ production by modulating amyloid precursor protein (APP) processing. Therefore, ARC-18 holds promise as a potential therapeutic agent for Alzheimer's disease.

5 × FAD mice; ARC-18; Adiponectin receptor 1; Alzheimer’s disease; Autophagy.