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

[Speaker] Xiaoling Gao:1
[Co-author] Lei Yao:1, Meng Hu:1, Xiao Gu:1
1:Shanghai Jiao Tong University School of Medicine, China

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 (Abeta) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Abeta clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that alpha-mangostin (alpha-M), a polyphenolicxanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Abeta clearance. However, the in vivo application of alpha-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, alpha-M was encapsulatedinto the core ofpoly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(alpha-M)]. Such nanoencapsulation improved the biodistribution of alpha-M in both the brain and liver, enhanced the brain clearance of 125I-radiolabeled Abeta1-42 in an LDLR-dependent manner, reduced Abeta 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 Abeta clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD.
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