Antroquinonol administration in animal preclinical studies for Alzheimer's disease (AD): A new avenue for modifying progression of AD pathophysiology

Fernandez Francesca; Aust Caitlin; Lye Sarah; Griffiths Lyn Robyn

doi:10.1016/j.bbih.2022.100435

Antroquinonol administration in animal preclinical studies for Alzheimer's disease (AD): A new avenue for modifying progression of AD pathophysiology

Brain Behav Immun Health. 2022 Feb 24:21:100435. doi: 10.1016/j.bbih.2022.100435. eCollection 2022 May.

Authors

Fernandez Francesca^{1

2}, Aust Caitlin^{1

2}, Lye Sarah^{1

2}, Griffiths Lyn Robyn²

Affiliations

¹ School of Behavioural and Health Sciences, Faculty of Health Sciences, Australian Catholic University, 1100 Nudgee Rd, Banyo, Queensland, 4014, Australia.
² Centre for Genomics and Personalised Medicine, Genomics Research Centre, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD, 4059, Australia.

Abstract

Despite the rise of Alzheimer's disease (AD) in an ageing population, no cure is currently available for this disorder. This study assessed the role of a natural compound, Antroquinonol, in modifying the progression of AD when administered at the start and/or before appearance of symptoms and when the disease was well established, in a transgenic animal model. Antroquinonol was administered daily for 8 weeks, in 11 week (early stage) and 9 month (late stage) male transgenic mice (3 times Transgenic mice PS1_M146V, APP_Swe, and tau_P301L, 3 Tg XAD) and their respective aged controls. Behavioural testing (including Elevated Plus Maze Watermaze, Recognition object testing and Y maze) was performed at the end of the drug administration. In addition AD biomarkers (Amyloid beta 42 (Aβ42), tau and phospho-tau levels), oxidative stress and inflammatory markers, were assessed in tested mice brains after their sacrifice at the end of the treatment. When administered before the start of symptoms at 11 weeks, Antroquinonol treatment at 34 mg/kg (D2) and more consistently at 75 mg/kg (D3), had a significant effect on reducing systemic inflammatory markers (Interleukin 1, IL-1β and TNF-α) and AD biomarker (Amyloid Beta 42, Aβ42 and tau) levels in the brain. The reduction of behavioural impairment reported for 3TgXAD mice was observed significantly for the D3 drug dose only and for all behavioural tests, when administered at 11 weeks. Similarly, beneficial effects of Antroquinonol (at higher dose D3) were noted in the transgenic mice in terms of AD biomarkers (tau and phosphorylated-tau), systemic inflammatory (IL-1β), brain anti-inflammatory (Nrf2) and oxidative (3-Nitrotyrosine, 3NT) markers. Improvement of memory impairment was also reported when Antroquinonol (D3) was administered at late stage (9 months). Since Antroquinonol has been used without adverse effects in previous successful clinical trials, this drug may offer a new avenue of treatment to modify AD development and progression.

Keywords: AD biomarkers; AICD, APP Intracellular Cytoplasmic/C-terminal Domain; AMPK, 5′ adenosine monophosphate-activated protein kinase; APP, Amyloid precursor protein; APPβ, secreted amino-terminals APPβ fragment; Alzheimer's disease (AD); Animal model of AD; Antroquinonol; Aβ, amyloid-β peptides; Behavioural testing; CTFα, carboxyterminal fragment-α; CTFβ, carboxyterminal fragment-β; GSK3β, Glycogen synthase kinase 3 beta; IFNγ, Interferon gamma; IL-1, Interleukin 1; IL-6, Interleukin 6; Inflammatory markers; MAPK, Mitogen activated protein kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA Rc, methyl-D-aspartate receptors receptor; ROS, reactive oxygen species; TNF-α, Tumor Necrosis factor alpha; Transgenic mice; cdck5, cyclin dependant kinase 5; sAPPα, secreted amino-terminals APPα fragment.