Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance

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• 作者：Lei Yao^a ; ¹ ; Xiao Gu^a ; ¹ ; Qingxiang Song^a ; Xiaolin Wang^a ; Meng Huang^a ; Meng Hu^a ; Lina Hou^a ; Ting Kang^b ; Jun Chen^b ; Hongzhuan Chen^a ; ^{hongzhuan_chen@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Xiaoling Gao^a ; ^{shellygao1@sjtu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Alzheimer's disease ; α-Mangostin ; Nanoparticles ; Amyloid-beta clearance ; Low-density lipoprotein receptor
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 March 2016
• 年：2016
• 卷：226
• 期：Complete
• 页码：1-14
• 全文大小：3644 K

文摘

Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)–poly(l-lactide) (PEG–PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of ¹²⁵I-radiolabeled Aβ_1–42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD.