Original ArticleThe hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach 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.
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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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.