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

https://doi.org/10.1016/j.nano.2015.09.003Get rights and content

Abstract

We previously showed the ability of liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide (mApoE-PA-LIP) to reduce brain Aβ in transgenic Alzheimer mice. Herein we investigated the efficacy of mApoE-PA-LIP to withdraw Aβ peptide in different aggregation forms from the brain, using a transwell cellular model of the blood–brain barrier and APP/PS1 mice. The spontaneous efflux of Aβ oligomers (Aβo), but not of Aβ fibrils, from the ‘brain’ side of the transwell was strongly enhanced (5-fold) in presence of mApoE-PA-LIP in the ‘blood’ compartment. This effect is due to a withdrawal of Aβo exerted by peripheral mApoE-PA-LIP by sink effect, because, when present in the brain side, they did not act as Aβo carrier and limit the oligomer efflux. In vivo peripheral administration of mApoE-PA-LIP significantly increased the plasma Aβ level, suggesting that Aβ-binding particles exploiting the sink effect can be used as a therapeutic strategy for Alzheimer disease.

From the Clinical Editor

Alzheimer disease (AD) at present is an incurable disease, which is thought to be caused by an accumulation of amyloid-β (Aβ) peptides in the brain. Many strategies in combating this disease have been focused on either the prevention or dissolving these peptides. In this article, the authors showed the ability of liposomes bi-functionalized with phosphatidic acid and with an ApoE- derived peptide to withdraw amyloid peptides from the brain. The data would help the future design of more novel treatment for Alzheimer disease.

Graphical abstract

The most culprit Aβ assemblies, soluble Aβ oligomers, are in equilibrium between the brain and the blood across the blood–brain barrier. Impairment in the clearance of Aβ from the brain, that promotes its aggregation to plaques, has been suggested to contribute to the onset/progression of Alzheimer disease. A therapeutic strategy based on sequestering peripheral soluble Aβ assemblies by using multi-functional nanoparticles may draw out Aβ excess from the brain and from the cerebral blood vessel via sink effect.

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Section snippets

Materials

All chemical reagents were from Sigma–Aldrich, Milano, Italy. Bovine brain sphingomyelin (Sm), cholesterol (Chol) and 1,2-stearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(poly(ethylene glycol)-2000)] (mal-PEG-PE) were purchased from Avanti Polar Lipids (USA). Dimyristoyl phosphatidic acid (PA), Aβ1 -42 peptide and 1,1,3,3,3-hexafluoro-2-propanol (HFIP) were purchased from Sigma–Aldrich, Milano, Italy. [3H]-propranolol and [3H]-Sm were purchased from PerkinElmer. FITC-dextran and bovine

Characterization of liposomes

In the present study, we utilized previously described mono- and bi-functionalized liposomes: PA-LIP, mApoE-LIP and mApoE-PA-LIP.6, 16, 24 Non-functionalized LIP have been used as a control. Size, polydisperisity and ζ-potential values are reported in Table 1. DLS analysis showed that LIP were monodispersed and their size remained constant, within the experimental error, for up to 5 days (data not shown). The yield of LIP surface functionalization with mApoE peptide ranged between 50% and 60%,

Discussion

The clearance of Aβo, the most culprit Aβ assembly, from the brain and/or from cerebral blood vessels is considered a primary therapeutic target to counteract the onset/progression of AD.

As already suggested by Matzuoka et al.,8 a possible strategy to reduce Aβo is to exploit the peripheral-sink effect using Aβ-binding agents. In the present investigation we evaluated the possibility to utilize nanoparticles6, 22 for this purpose, using an in vitro BBB transwell model and APP/PS1 as animal

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  • Cited by (0)

    The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement no. 212043 (NAD) and by Banca Intesa SanPaolo, grant 2014-2015 (to MS).

    The authors report no conflicts of interest in this work.

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