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

  • Mol Neurobiol. 2026 Feb 14;63(1):438. doi: 10.1007/s12035-026-05731-0.
Shangming Li  1  2 ,  Bocheng Xiong  1 ,  Nan Xu  2 ,  Lulin Nie  1 ,  Kaiwu He  1 ,  Guiliang Zhang  2 ,  Chongyang Chen  1 ,  Zaijun Zhang  3 ,  Maggie Pui Man Hoi  4 ,  Xifei Yang  5
Affiliations
  • 1. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universiade, Taipa, Macau, N22-7012, China.
  • 3. Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, Institute of New Drug Research, College of Pharmacy, Jinan University, Guangdong, China.
  • 4. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universiade, Taipa, Macau, N22-7012, China. [email protected].
  • 5. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China. [email protected].
PMID: 41689616 DOI: 10.1007/s12035-026-05731-0
Abstract

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 (sAPPβ, 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.

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