Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models

J Neurosci. 2014 Oct 15;34(42):14022-31. doi: 10.1523/JNEUROSCI.0284-14.2014.

Abstract

Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Aβ oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease.

Keywords: Abeta; Alzheimer; cognitive impairment; liposomes; nanomedicine; oligomers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apolipoproteins E / administration & dosage*
  • Apolipoproteins E / metabolism
  • Disease Models, Animal*
  • Liposomes / administration & dosage*
  • Liposomes / metabolism
  • Male
  • Memory Disorders / drug therapy*
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / drug therapy*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Random Allocation

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Liposomes
  • Peptide Fragments
  • amyloid beta-protein (1-42)