title: Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.
abstract: 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 (125)I-radiolabeled Aβ1-42 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.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Lina
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China. Electronic address: hongzhuan_chen@hotmail.com.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China. Electronic address: shellygao1@sjtu.edu.cn.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000032:analysis / Q000378:metabolism; D044004:Xanthones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D004337:Drug Carriers; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; D044004:Xanthones; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; C021053:mangostin
keywords: Alzheimer's disease; Amyloid-beta clearance; Low-density lipoprotein receptor; Nanoparticles; α-Mangostin