“This is a very exciting study that clearly shows that a nanoparticle capable of inducing autophagy and binding Aβ42 can clear amyloid plaques and rescue cognitive capacity,” commented Claudia Almeida of the University of Lisbon in Portugal. The treated animals performed at near wild-type levels on the Morris water maze test of spatial memory, a benefit still seen two months after treatment stopped. Compared with control AD mice, treated animals had roughly fivefold less soluble and insoluble Aβ42, and fewer plaques. To assess the nanosweepers’ Aβ-clearing ability, the researchers treated nine-month-old AD mice every other day for a month. However, this seemingly small amount was sufficient to trigger autophagy in hippocampal neurons, as evidenced by elevated autophagy markers.ĭeliverance-to Destruction? Nanosweepers (red) entered neuroblastoma cells and co-localized with p62 (green), a marker of autophagolysosomes. Under these conditions, roughly 2 percent of the injected nanosweepers reached the brain. Would this work in the brain? The researchers injected the nanosweepers intravenously into wild-type and APPSwe/PS11de9 mice, along with cyclosporine, a compound known to enhance permeability of the blood-brain barrier. Finally, the researchers observed the internalized nanosweepers trapped inside autophagosomes. Immunofluorescence experiments showed that nanosweepers adorned with just the KLVFF peptide triggered uptake of Aβ42 into neuroblastoma cells, but that beclin-1 was required to switch on autophagy. Using biochemical and structural techniques, they confirmed that the KLVFF moiety captured Aβ42 and prevented its aggregation in solution. The researchers next investigated how the nanosweeper worked. A nanosweeper particle adorned with beclin-1 (red), as well as a complementary peptide (blue) to catch Aβ (green), triggers its own destruction via autophagy. ![]() ![]() Both the beclin-1 and KLVFF components were required to achieve maximal protection. While nearly half of the cells succumbed to Aβ42 in the absence of the nanosweeper, nearly all survived in their presence. In cell culture, these nanosweepers protected mouse neuroblastoma cells from Aβ42 toxicity. In addition to beclin-1, the researchers coated these particles with the KLVFF peptide, which adheres to Aβ and prevents its aggregation ( Xie et al., 2015). The researchers designed beclin-1-coated nanoparticles to divert extracellular Aβ into this disposal stream.Īt their core, the nanoparticles were made of chitosan, a cationic polymer derived from the chitin that gives crustacean shells their toughness. Beclin-1, which is reduced in the AD brain, activates phagocytosis and autophagy, facilitating the internalization of extracellular debris as well as its digestion ( Jun 2010 news Sep 2013 news). Though Aβ accumulates outside of cells, some cells, such as microglia, engulf the peptide and clear it via autophagy. "Swept" mice had fewer memory problems.Ĭo-first authors Qiang Luo, Yao-Xin Lin, and Pei-Pei Yang designed the nanosweeper to take advantage of autophagy, the cell’s primary means of disposing of its own detritus.In mice, nanosweepers entered the brain and reduced Aβ burden. ![]() ![]() Tiny particles called nanosweepers captured Aβ, triggered its uptake into cells, and switched on autophagy.
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