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A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models.
Aging Cell. 2020 02; 19(2):e13069.AC

Abstract

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Authors+Show Affiliations

Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China. Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and 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. Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. Division of Mycobiology & Neurodegenerative Disease Research, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur, India.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31858697

Citation

Song, Ju-Xian, et al. "A Small Molecule Transcription Factor EB Activator Ameliorates Beta-amyloid Precursor Protein and Tau Pathology in Alzheimer's Disease Models." Aging Cell, vol. 19, no. 2, 2020, pp. e13069.
Song JX, Malampati S, Zeng Y, et al. A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models. Aging Cell. 2020;19(2):e13069.
Song, J. X., Malampati, S., Zeng, Y., Durairajan, S. S. K., Yang, C. B., Tong, B. C., Iyaswamy, A., Shang, W. B., Sreenivasmurthy, S. G., Zhu, Z., Cheung, K. H., Lu, J. H., Tang, C., Xu, N., & Li, M. (2020). A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models. Aging Cell, 19(2), e13069. https://doi.org/10.1111/acel.13069
Song JX, et al. A Small Molecule Transcription Factor EB Activator Ameliorates Beta-amyloid Precursor Protein and Tau Pathology in Alzheimer's Disease Models. Aging Cell. 2020;19(2):e13069. PubMed PMID: 31858697.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models. AU - Song,Ju-Xian, AU - Malampati,Sandeep, AU - Zeng,Yu, AU - Durairajan,Siva Sundara Kumar, AU - Yang,Chuan-Bin, AU - Tong,Benjamin Chun-Kit, AU - Iyaswamy,Ashok, AU - Shang,Wen-Bin, AU - Sreenivasmurthy,Sravan Gopalkrishnashetty, AU - Zhu,Zhou, AU - Cheung,King-Ho, AU - Lu,Jia-Hong, AU - Tang,Chunzhi, AU - Xu,Nenggui, AU - Li,Min, Y1 - 2019/12/19/ PY - 2019/07/22/received PY - 2019/09/30/revised PY - 2019/10/24/accepted PY - 2019/12/21/pubmed PY - 2020/11/21/medline PY - 2019/12/21/entrez KW - Alzheimer's disease KW - MAPT/Tau KW - TFEB KW - beta-amyloid KW - curcumin analog C1 SP - e13069 EP - e13069 JF - Aging cell JO - Aging Cell VL - 19 IS - 2 N2 - Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD. SN - 1474-9726 UR - https://www.unboundmedicine.com/medline/citation/31858697/A_small_molecule_transcription_factor_EB_activator_ameliorates_beta_amyloid_precursor_protein_and_Tau_pathology_in_Alzheimer's_disease_models_ L2 - https://doi.org/10.1111/acel.13069 DB - PRIME DP - Unbound Medicine ER -