TY - JOUR
T1 - Twendee X Ameliorates Phosphorylated Tau, α-Synuclein and Neurovascular Dysfunction in Alzheimer's Disease Transgenic Mice With Chronic Cerebral Hypoperfusion
AU - Liu, Xia
AU - Yamashita, Toru
AU - Shang, Jingwei
AU - Shi, Xiaowen
AU - Morihara, Ryuta
AU - Huang, Yong
AU - Sato, Kota
AU - Takemoto, Mami
AU - Hishikawa, Nozomi
AU - Ohta, Yasuyuki
AU - Abe, Koji
N1 - Funding Information:
Financial Disclosure: This work was partly supported by a Grant-in-Aid for Scientific Research (B) 17H04196, (C) 17K10827 and Challenging Research 15K15527, and by Grants-in-Aid from the Research Committees (Mizusawa H, Nishizawa M, Sasaki H, and Aoki M) from the Ministry of Health, Labour and Welfare of Japan.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/10
Y1 - 2019/10
N2 - Background: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). Methods: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. Results: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; # P < .05 and ## P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; # P < .05, and ## P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. Conclusions: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.
AB - Background: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). Methods: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. Results: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; # P < .05 and ## P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; # P < .05, and ## P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. Conclusions: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.
KW - APP23 mice
KW - Alzheimer's disease
KW - chronic cerebral hypoperfusion
KW - neurovascular dysfunction
KW - phosphorylated tau
KW - α-synuclein
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U2 - 10.1016/j.jstrokecerebrovasdis.2019.104310
DO - 10.1016/j.jstrokecerebrovasdis.2019.104310
M3 - Article
C2 - 31383622
AN - SCOPUS:85072545723
VL - 28
JO - Journal of Stroke and Cerebrovascular Diseases
JF - Journal of Stroke and Cerebrovascular Diseases
SN - 1052-3057
IS - 10
M1 - 104310
ER -