TY - JOUR
T1 - Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in alzheimer’s disease mouse models
AU - Balducci, Claudia
AU - Mancini, Simona
AU - Minniti, Stefania
AU - La Vitola, Pietro
AU - Zotti, Margherita
AU - Sancini, Giulio
AU - Mauri, Mario
AU - Cagnotto, Alfredo
AU - Colombo, Laura
AU - Fiordaliso, Fabio
AU - Grigoli, Emanuele
AU - Salmona, Mario
AU - Snellman, Anniina
AU - Haaparanta-Solin, Merja
AU - Forloni, Gianluigi
AU - Masserini, Massimo
AU - Re, Francesca
PY - 2014/10/15
Y1 - 2014/10/15
N2 - 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.
AB - 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.
KW - Abeta
KW - Alzheimer
KW - Cognitive impairment
KW - Liposomes
KW - Nanomedicine
KW - Oligomers
UR - http://www.scopus.com/inward/record.url?scp=84907983707&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907983707&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0284-14.2014
DO - 10.1523/JNEUROSCI.0284-14.2014
M3 - Article
C2 - 25319699
AN - SCOPUS:84907983707
VL - 34
SP - 14022
EP - 14031
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 42
ER -