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Exploring the Anti-Alzheimer's Disease Effects of Nano-Honokiol on TgCRND8 Transgenic Mice: Focusing on Gut Microbiota.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Exploring the Anti-Alzheimer's Disease Effects of Nano-Honokiol on TgCRND8 Transgenic Mice: Focusing on Gut Microbiota./
作者:	Qu, Chang.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	238 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-10, Section: B.
Contained By:	Dissertations Abstracts International83-10B.
標題:	Medicine. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29186005
ISBN:	9798426800670

Exploring the Anti-Alzheimer's Disease Effects of Nano-Honokiol on TgCRND8 Transgenic Mice: Focusing on Gut Microbiota.
Qu, Chang.

Exploring the Anti-Alzheimer's Disease Effects of Nano-Honokiol on TgCRND8 Transgenic Mice: Focusing on Gut Microbiota. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 238 p.

Source: Dissertations Abstracts International, Volume: 83-10, Section: B.

Thesis (Ph.D.)--The Chinese University of Hong Kong (Hong Kong), 2021.

This item is not available from ProQuest Dissertations & Theses.

Alzheimer's disease (AD) is the most common form of dementia in the older population in the world. Currently no curative disease modifying therapeutics are available for this devastating neurodegenerative disease. Deranged gut microbiota has been demonstrated in recent years to cause brain dysfunction in AD development. Moreover, gut microbiota-derived metabolites, such as neurotransmitters, amino acids, organic acids, are notably altered in blood samples in neurodegenerative diseases. Therefore, targeting potential biomarkers and metabolites from gut microbiota may be a promising approach for development of novel AD therapeutics. The present study first aimed to investigate the mechanistic link between AD-like amyloid pathology and gut microbiota in TgCNRD8 transgenic mice. Our results demonstrated that gut dysbiosis occurred in TgCRND8 mice of 2, 4, 6, 8, 10, 12 months old, and was age-dependently associated with escalation of the CDK5/STAT3 signaling pathway in the brain of TgCRND8 mice. In addition, microbiota-derived metabolite Trimethylamine-N-oxide (TMAO) changed significantly according to untargeted metabolism analysis, and the alteration in turn affected choline metabolism in TgCRND8 mice. Furthermore, fecal microbiota transplantation (FMT) treatment revealed that the microbiota from aged TgCRND8 mice accelerated the cognitive deficits and neuropathology in young TgCRND8 mice, accompanied by activating CDK5/STAT3 signaling in the brain. FMT treatment with feces from WT mice to TgCRND8 mice improved their cognitive functions, attenuated amyloidogenic processes and diminished the CDK5/STAT3 signaling pathway. Finally, excessive choline supplementation accelerated cognitive and motility dysfunction, enlarged Abstract iii amyloid aggregation and neuroinflammation in both of the brain and gut via exaggerating CDK5/STAT3 pathway. Honokiol (HO) is a promising anti-AD lignan isolated from Magnoliae Officinalis Cortex and exerts potent neuroprotective efficacy in AD animal models. However, its poor dissolution poses a big challenge as this limits its bioavailability. Therefore in this study, we applied nano drug delivery system (Nano-DDS) when preparing HO solution (Nano-HO) to improve its poor solubility. The current project also aimed to investigate the cognition-improving effect of Nano-HO on TgCRND8 transgenic mice, and elucidate the molecular mechanisms underlying its neuroprotective action. Drug or vehicle treatment were administered intragastrically over a period of 17 weeks to male WT or TgCRND8 transgenic mice at 3-month-old, and the Morris water maze test (MWMT) was then conducted to assess cognitive functions. After Nano-HO treatment, its oral bioavailability was greatly improved when compared with HO suspension treatment, and the cognitive dysfunction and neuroinflammation in TgCRND8 mice were markedly alleviated via reducing the contents of TNF-α, IL-6 and IL-1β in the brain, suppressing the abnormal activation of microglia and astrocytes, and diminishing the deposition of Aβ plaques. Notably, as compared to HO-suspension, Nano-HO exerted more potent efficacy in regulating amyloid precursor protein (APP) processing by suppressing β-secretase and enhancing Aβ-degrading enzymes. Also, Nano-HO treatment showed more potent effect in inhibiting tau hyperphosphorylation at site Thr 205 and regulating apoptosis proteins including caspase-3 and Bcl-2. Furthermore, Nano-HO treatment more potently attenuated the expressions of p-JNK and p-35, while enhanced the level of p-GSK-3β (Ser 9). Most importantly, Nano-HO treatment more effectively prevented the gut dysbiosis in TgCRND8 mice than regular Abstract iv HO-suspension treatment. Taken together, our results for the first time revealed that gut dysbiosis is closely associated with cognitive dysfunction in TgCRND8 mice in an age-dependent manner. Moreover, we demonstrated that Nano-HO exerted more potent neuroprotective effect in recovering cognitive impairments in TgCRND8 mice than regular HO-suspension, at least partially via suppressing JNK/CDK5/GSK-3β signaling pathway and modulating gut microbiota community. These results indicate that Nano-HO is a promising drug worthy of further development into pharmaceutical agent for AD treatment.

ISBN: 9798426800670Subjects--Topical Terms:

641104
Medicine.
Subjects--Index Terms:

Gut microbiome

Exploring the Anti-Alzheimer's Disease Effects of Nano-Honokiol on TgCRND8 Transgenic Mice: Focusing on Gut Microbiota.
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