2. Academic Validation
  3. Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease

  • Signal Transduct Target Ther. 2023 Oct 23;8(1):404. doi: 10.1038/s41392-023-01657-4.
Ashok Iyaswamy # 1,  Abhimanyu Thakur # 2 3,  Xin-Jie Guan 4,  Senthilkumar Krishnamoorthi 4,  Tsz Yan Fung 4,  Kejia Lu 4,  Isha Gaurav 5,  Zhijun Yang 5,  Cheng-Fu Su 4,  Kwok-Fai Lau 6,  Kui Zhang 7 8,  Roy Chun-Laam Ng 9,  Qizhou Lian 10 11 12,  King-Ho Cheung 4,  Keqiang Ye 13,  Huanhuan Joyce Chen 14 15,  Min Li 16
Affiliations

Affiliations

  • 1 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. [email protected].
  • 2 Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, USA. [email protected].
  • 3 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. [email protected].
  • 4 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
  • 5 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
  • 6 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 7 Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, USA.
  • 8 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • 9 Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
  • 10 Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 11 Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 12 HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
  • 13 Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 14 Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL, USA. [email protected].
  • 15 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. [email protected].
  • 16 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. [email protected].
  • # Contributed equally.
PMID: 37867176 DOI: 10.1038/s41392-023-01657-4
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated Tau Protein, and neurofibrillary tangles in the brain. The overexpression of Amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of Amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30-200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood-brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an Autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced Autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

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