Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models

Abstract

Alzheimer's disease is characterized by the accumulation and deposition of plaques of ␤-amyloid (A␤) peptide in the brain. Given its pivotal role, new therapies targeting A␤ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of A␤ assemblies and evaluated their efficiency in reducing the A␤ 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␤ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, A␤ 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␤ 1-42 (Ϫ33%), assessed by ELISA, and the number and total area of plaques (Ϫ34%) detected histologically. Also, brain A␤ oligomers were reduced (Ϫ70.5%), 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 A␤ was associated with its increase in liver (ϩ18%) and spleen (ϩ20%). 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␤ 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.

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…For AD, 26 full-text article reviews were performed, and 12 studies were included for their fulfillment of inclusion criteria ( Figure 3, Table 3). 80,[83][84][85][86][87][88][89][90][91][92][93][94][95] For PD, 19 full-text articles were reviewed, and eight articles had all the requisites to be considered here ( Figure 3, Table 3). [96][97][98][99][100][101][102][103] Unfortunately, for Huntington's disease, just one full article was analyzed and this article did not show any outcome of interest for this disease, and for this reason was not included here ( Figure 3).…”

“…[93][94][95] Moreover, there have been several studies exploring different strategies to block the effects of Aβ and tau proteins that constitute major hallmarks of AD. [84][85][86][87]91 Once encapsulated into liposomes, the H102 peptide, a β-sheet breaker, was able to block the early steps of aggregation and misfolding of the soluble Aβ, improving the spatial memory impairment of AD in rats. 112 α-Mangostin is a polyphenolic xanthone that exhibits pharmacological effects, such as anti-inflammation, antioxidant, and antitumor effects.…”

“…83 It has also been demonstrated that bifunctionalized liposomes decorated with phosphatidic acid and a modified ApoE-derived peptide are able to cross the BBB in vivo and destabilize Aβ aggregates, suggesting that this approach is a good option for AD treatment. 84,85 Although the scope of this review is on liposome-strategies with the aim of facilitating BBB crossing, it is important to mention that other strategies have been developed for the use of liposomes for AD treatment. 89,[113][114][115][116] Curcumin is a natural compound extract from the plant Curcuma longa, and has been reported to be a fluorescent molecule with high affinity for the Aβ peptide and able to reduce Aβ aggregation.…”

The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease

“…APP/PS1 mice (n = 7 mice/group) were intraperitoneally (I.P.) injected once every other day with mApoE-PA-LIP (100 μl, 73.5 mg of total lipids/kg) or with PBS as a control (100 μl), as already described, 22 with changes concerning the age of animals (16 months of age) and the duration of the treatment (two weeks). At the end of treatment, animals were sacrificed and blood was collected by cardiac puncture and processed for plasma separation.…”

“…At the end of treatment, animals were sacrificed and blood was collected by cardiac puncture and processed for plasma separation. Brains were dissected, weighed and processed to extract Aβ 22 Aβ levels in plasma and brain were quantified by ELISA assay, as described.…”