| First Author | Balducci C | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 42 | Pages | 14022-31 |
| PubMed ID | 25319699 | Mgi Jnum | J:348876 |
| Mgi Id | MGI:7645572 | Doi | 10.1523/JNEUROSCI.0284-14.2014 |
| Citation | Balducci C, et al. (2014) Multifunctional liposomes reduce brain beta-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models. J Neurosci 34(42):14022-31 |
| abstractText | Alzheimer's disease is characterized by the accumulation and deposition of plaques of beta-amyloid (Abeta) peptide in the brain. Given its pivotal role, new therapies targeting Abeta are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Abeta assemblies and evaluated their efficiency in reducing the Abeta 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 Abeta binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Abeta 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 Abeta1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Abeta 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 Abeta 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 Abeta 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. |
