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

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.

Liposome delivery systems for the treatment of Alzheimer’s disease

“…Aβ oligomers were found to be transported out of the brain, across the BBB, with mApoE-PA-LIP acting in the periphery to mediate a fivefold increase in this efflux. 74 This provides an insight into future therapies that may only require sequestration of Aβ in the plasma, without the need to cross the BBB. It is evident, however, that this therapy might slow down neurodegeneration, but does not eliminate the cause of Aβ overproduction.…”

Functionalized liposomes and phytosomes loading Annona muricata L. aqueous extract: Potential nanoshuttles for brain-delivery of phenolic compounds

“…hCMEC/D3 cells were used as a representative human BBB model. They were cultured at 37°C, 5% CO 2 /saturated humidity in EBM-2 medium supplemented with 5% FBS, 1% pen-strep, 1.4 µM hydrocortisone, 5 µg/ml ascorbic acid, 1/100 chemically defined lipid concentrate, 10 mM HEPES and 1 ng/ml basic FGF (Bana et al, 2014;Mancini et al, 2016). For the MTT assays, cells (passage 25-35) were seeded in a collagen coated 96 well-plate at a density of 10,000 cells/ well.…”

Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for the treatment of Alzheimer's disease

“…Aβ oligomers were prepared as previously described. 3,14 Briefly, Aβ 1-42 (Sigma-Aldrich Co., St Louis, MO, USA) lyophilized peptide was solubilized in 1,1,3,3,3-hexafluoro-2-propanol (HFIP, Sigma-Aldrich Co) at 1 mg/mL concentration. The peptide was allowed to air dry in a chemical fume hood overnight and suspended in dimethyl sulfoxide (DMSO; Sigma-Aldrich Co) in order to obtain a peptide concentration of 5 mM.…”

“…The formation of oligomers was assessed by atomic force microscopy as described. 3,14 effect of treatment with multifunctional lIPs on cell viability Cortical neural cells were plated on 96 wells at a density of 5,000 cells/well and kept in a controlled environment (37°C and 5% CO 2 ). At DIV6, cells were exposed for 4 or 48 h to the medium containing mApoE-PA-LIPs at a concentration of 10 µM.…”