Alzheimer’s disease is characterized by the accumulation and deposition of plaques of/3-amyloid (A/3) peptide in the brain. Given its pivotal role, new therapies targeting A/3 are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A/3 assemblies and evaluated their efficiency in reducing the A/3 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 A/3 binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A/3 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 A/31– 42 (—33%), assessed by ELISA, and the number and total area of plaques (—34%) detected histologically. Also, brain A/3 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 [11C]Pittsburgh compound B (PIB). The reduction of brain A/3 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 A/3 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.

Balducci, C., Mancini, S., Minniti, S., La Vitola, P., Zotti, M., Sancini, G., et al. (2014). Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in alzheimer’s disease mouse models. THE JOURNAL OF NEUROSCIENCE, 34(42), 14022-14031 [10.1523/JNEUROSCI.0284-14.2014].

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

MANCINI, SIMONA
Secondo
;
MINNITI, STEFANIA;SANCINI, GIULIO ALFREDO;MAURI, MARIO;MASSERINI, MASSIMO ERNESTO
Penultimo
;
RE, FRANCESCA
Ultimo
2014

Abstract

Alzheimer’s disease is characterized by the accumulation and deposition of plaques of/3-amyloid (A/3) peptide in the brain. Given its pivotal role, new therapies targeting A/3 are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A/3 assemblies and evaluated their efficiency in reducing the A/3 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 A/3 binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A/3 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 A/31– 42 (—33%), assessed by ELISA, and the number and total area of plaques (—34%) detected histologically. Also, brain A/3 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 [11C]Pittsburgh compound B (PIB). The reduction of brain A/3 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 A/3 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.
Articolo in rivista - Articolo scientifico
Abeta; Alzheimer; Cognitive impairment; Liposomes; Nanomedicine; Oligomers; Neuroscience (all)
English
2014
34
42
14022
14031
none
Balducci, C., Mancini, S., Minniti, S., La Vitola, P., Zotti, M., Sancini, G., et al. (2014). Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in alzheimer’s disease mouse models. THE JOURNAL OF NEUROSCIENCE, 34(42), 14022-14031 [10.1523/JNEUROSCI.0284-14.2014].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/74927
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