Indole Compound NC009-1 Augments APOE and TRKA in Alzheimer’s Disease Cell and Mouse Models for Neuroprotection and Cognitive Improvement

Article type: Research Article

Authors: Chen, Yi-Chun^{a; 1} | Chiu, Ya-Jen^{b; 1} | Lin, Chih-Hsin^a | Hsu, Wen-Chuin^{a; c} | Wu, Jia-Lu^b | Huang, Chen-Hsiang^b | Lin, Chia-Wei^b | Yao, Ching-Fa^d | Huang, Hei-Jen^e | Lo, Yen-Shi^a | Chen, Chiung-Mei^a | Wu, Yih-Ru^a | Chang, Kuo-Hsuan^{a; *} | Lee-Chen, Guey-Jen^{b; *} | Mei Hsieh-Li, Hsiu^{b; *}

Affiliations: [a] Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan | [b] Department of Life Science, National Taiwan Normal University, Taipei, Taiwan | [c] Dementia Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan | [d] Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan | [e] Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan

Correspondence: [*] Correspondence to: Kuo-Hsuan Chang, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan. E-mail: [email protected] and Guey-Jen Lee-Chen and Hsiu Mei Hsieh-Li, National Taiwan Normal University, Taipei 11677, Taiwan. E-mails: [email protected] (G.-J. Lee-Chen) and [email protected] (H.M. Hsieh-Li).

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD), associated with abnormal accumulation of amyloid-β (Aβ), is the most common cause of dementia among older people. A few studies have identified substantial AD biomarkers in blood but their results were inconsistent. Here we screened gene expression alterations on Aβ-GFP SH-SY5Y neuronal model for AD, and evaluated the findings on peripheral leukocytes from 78 patients with AD and 56 healthy controls. The therapeutic responses of identified biomarker candidates were further examined in Aβ-GFP SH-SY5Y neuronal and APP/PS1/Tau triple transgenic (3×Tg-AD) mouse models. Downregulation of apolipoprotein E (APOE) and tropomyosin receptor kinase A (TRKA) were detected in Aβ-GFP SH-SY5Y cells and validated by peripheral leukocytes from AD patients. Treatment with an in-house indole compound NC009-1 upregulated the expression of APOE and TRKA accompanied with improvement of neurite outgrowth in Aβ-GFP SH-SY5Y cells. NC009-1 further rescued the downregulated APOE and TRKA and reduced Aβ and tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin-induced hyperglycemic 3×Tg-AD mice. These results suggest the role of APOE and TRKA as potential peripheral biomarkers in AD, and offer a new drug development target of AD treatment. Further studies of a large series of AD patients will be warranted to verify the findings and confirm the correlation between these markers and therapeutic efficacy.

Keywords: Alzheimer’s disease, amyloid-β, APOE, biomarker, indole compound, TRKA

DOI: 10.3233/JAD-180643

Journal: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 737-756, 2019