Tyrosol Reduces Amyloid-β Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer’s Disease Model Mice

Article type: Research Article

Authors: Taniguchi, Kaori^a | Yamamoto, Fumiko^{a; b} | Arai, Takuya^a | Yang, Jinwei^c | Sakai, Yusuke^c | Itoh, Masayuki^d | Mamada, Naomi^b | Sekiguchi, Masayuki^e | Yamada, Daisuke^f | Saitoh, Akiyoshi^f | Kametani, Fuyuki^g | Tamaoka, Akira^b | Araki, Yumiko M.^h | Wada, Keiji^e | Mizusawa, Hidehiroⁱ | Araki, Wataru^{a; *}

Affiliations: [a] Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan | [b] Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan | [c] Tokiwa Phytochemical Co., Ltd, Sakura, Chiba, Japan | [d] Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan | [e] Department of Degenerative Neurological Diseases, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan | [f] Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan | [g] Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan | [h] Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University, Tokyo, Japan | [i] National Center Hospital, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan

Correspondence: [*] Correspondence to: Wataru Araki, Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan. E-mail: [email protected].

Abstract: Soluble amyloid-β (Aβ) oligomers (AβOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer’s disease (AD). Since AβOs are a key therapeutic target, we attempted to identify natural agents that reduce AβO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AβOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AβO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aβ accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AβO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.

Keywords: Alzheimer’s disease, amyloid-β, neuron, oligomer, oxidative stress, synapse

DOI: 10.3233/JAD-190098

Journal: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 937-952, 2019