GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular β-amyloid (Aβ) is crucial in AD pathogenesis, and Aβ-initiated secondary pathological processes could independently lead to neuronal degeneration and pathogenesis in AD. Thus, the development of combination therapeutics that can not only accelerate Aβ clearance but also simultaneously protect neurons or inhibit other subsequent pathological cascade represents a promising strategy for AD intervention. Here, we designed a nanostructure, monosialotetrahexosylganglioside (GM1)-modified reconstituted high density lipoprotein (GM1-rHDL), that possesses antibody-like high binding affinity to Aβ, facilitates Aβ degradation by microglia, and Aβ efflux across the blood-brain barrier (BBB), displays high brain biodistribution efficiency following intranasal administration, and simultaneously allows the efficient loading of a neuroprotective peptide, NAP, as a nanoparticulate drug delivery system for the combination therapy of AD. The resulting multifunctional nanostructure, αNAP-GM1-rHDL, was found to be able to protect neurons from Aβ(1-42) oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL in vitro and reduced Aβ deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both αNAP solution and GM1-rHDL in AD model mice following intranasal administration with no observable cytotoxicity noted. Taken together, this work presents direct experimental evidence of the rational design of a biomimetic nanostructure to serve as a safe and efficient multifunctional nanoplatform for the combination therapy of AD.

• Authors: Meng Huang, Meng Hu, Qingxiang Song, Huahua Song, Jialin Huang, Xiao Gu, Xiaolin Wang, Jun Chen, Ting Kang, Xingye Feng, Di Jiang, Gang Zheng, Hongzhuan Chen, Xiaoling Gao
• Journal: ACS nano (ACS Nano) Vol. 9 Issue 11 Pg. 10801-16 (Nov 24 2015) ISSN: 1936-086X [Electronic] United States
• PMID: 26440073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Apolipoproteins E
• Glutamates
• Lipoproteins, HDL
• Neuroprotective Agents
• Peptide Fragments
• Peptides
• amyloid beta-protein (1-42)
• G(M1) Ganglioside

Topics

• Administration, Intranasal
• Alzheimer Disease (complications, pathology, therapy)
• Amino Acid Sequence
• Amyloid beta-Peptides (metabolism)
• Animals
• Apolipoproteins E (metabolism)
• Brain (drug effects, metabolism)
• Combined Modality Therapy
• Disease Models, Animal
• Endocytosis (drug effects)
• G(M1) Ganglioside (administration & dosage, metabolism, pharmacokinetics)
• Glutamates (toxicity)
• Lipoproteins, HDL (administration & dosage, metabolism, pharmacokinetics)
• Memory Disorders (complications, drug therapy, pathology)
• Mice, Inbred ICR
• Microglia (drug effects, metabolism)
• Molecular Sequence Data
• Nanoparticles (chemistry, ultrastructure)
• Neuroprotection (drug effects)
• Neuroprotective Agents (pharmacology)
• Particle Size
• Peptide Fragments (metabolism)
• Peptides (chemistry)
• Rats, Sprague-Dawley
• Static Electricity
• Tissue Distribution (drug effects)