Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models
Ashok Iyaswamy,
Xueli Wang,
Senthilkumar Krishnamoorthi,
Venkatapathy Kaliamoorthy,
Sravan G. Sreenivasmurthy,
Siva Sundara Kumar Durairajan,
Ju-Xian Song,
Benjamin Chun-kit Tong,
Zhou Zhu,
Cheng-Fu Su,
Jia Liu,
King-Ho Cheung,
Jia-Hong Lu,
Jie-Qiong Tan,
Hung Wing Li,
Man Shing Wong,
Min Li
Affiliations
Ashok Iyaswamy
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China; Corresponding author. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Xueli Wang
Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China
Senthilkumar Krishnamoorthi
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Centre for Trans-disciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India
Venkatapathy Kaliamoorthy
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
Sravan G. Sreenivasmurthy
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
Siva Sundara Kumar Durairajan
Division of Mycobiology and Neurodegenerative Disease Research, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur, India
Ju-Xian Song
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
Benjamin Chun-kit Tong
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
Zhou Zhu
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
Cheng-Fu Su
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
Jia Liu
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
King-Ho Cheung
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China
Jia-Hong Lu
State Key Lab of Quality Research in Chinese Medicine, University of Macao, Macao
Jie-Qiong Tan
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Hung Wing Li
Department of Chemistry, The Chinese University of Hong Kong, Hong Kong SAR, China; Corresponding author. Department of Chemistry, The Chinese University of Hong Kong, Hong Kong SAR, China.
Man Shing Wong
Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China; Corresponding author. Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.
Min Li
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China; Corresponding author. School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aβ-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aβ aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aβ oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aβ, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.