Extracellular chaperones prevent Aβ42-induced toxicity in rat brains

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, formation of the extracellular amyloid β (Aβ42) plaques, neuronal and synapse loss, and activated microglia and astrocytes. Extracellular chaperones, which are known to inhibit amyloid fibril formation and promote clearance of misfolded aggregates, have recently been shown to reduce efficiently the toxicity of HypF-N misfolded oligomers to immortalised cell lines, by binding and clustering them into large species. However, the role of extracellular chaperones on Aβ oligomer toxicity remains unclear, with reports often appearing contradictory. In this study we microinjected into the hippocampus of rat brains Aβ42 oligomers pre-incubated for 1h with two extracellular chaperones, namely clusterin and α2-macroglobulin. The chaperones were found to prevent Aβ42-induced learning and memory impairments, as assessed by the Morris Water Maze test, and reduce Aβ42-induced glia inflammation and neuronal degeneration in rat brains, as probed by fluorescent immunohistochemical analyses. Moreover, the chaperones were able to prevent Aβ42 colocalisation with PSD-95 at post-synaptic terminals of rat primary neurons, suppressing oligomer cytotoxicity. All such effects were not effective by adding pre-formed oligomers and chaperones without preincubation. Molecular chaperones have therefore the potential to prevent the early symptoms of AD, not just by inhibiting Aβ42 aggregation, as previously demonstrated, but also by suppressing the toxicity of Aβ42 oligomers after they are formed. These findings elect them as novel neuroprotectors against amyloid-induced injury and excellent candidates for the design of therapeutic strategies against AD.

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

“…6B). These results are consistent with the results of a previous study showing that coincubation of preformed Aβ 1-42 oligomers with native α 2 M inhibits the subsequent binding of the oligomers to cells (19). Because the binding of native α 2 M to oxidized, oligomeric bAβ 1-42 is substantially greater than to monomeric bAβ (Fig.…”

“…It has previously been shown that native α 2 M protects neurons from Aβ 1-42 toxicity in vitro and in vivo (19). We find that, when tested at a molar ratio of α 2 M: β 1-42 of 1:150, oxidized α 2 M, but not native α 2 M, significantly protects SH-SY5Y neuroblastoma cells from Aβ 1-42 toxicity (Fig.…”

“…Several in vitro studies have shown that α 2 M can inhibit both fibril formation by amyloidogenic proteins and peptides (13)(14)(15)(16) and stress-induced amorphous aggregation of other systems (17). In addition, recent studies have shown that α 2 M can protect neurons from toxic oligomers of the protein HypF-N and the Alzheimer's diseaserelevant amyloid β-peptide (Aβ ) by preventing them from binding to the cell surface (18,19). This action is implicated in the ability of α 2 M to inhibit inflammatory responses of glia induced by Aβ in vitro and in vivo (19).…”

“…In addition, recent studies have shown that α 2 M can protect neurons from toxic oligomers of the protein HypF-N and the Alzheimer's diseaserelevant amyloid β-peptide (Aβ ) by preventing them from binding to the cell surface (18,19). This action is implicated in the ability of α 2 M to inhibit inflammatory responses of glia induced by Aβ in vitro and in vivo (19). α 2 M is also found colocalized with misfolded protein deposits in Alzheimer's disease (20), the spongiform encephalopathies (21), atherosclerosis (22), and arthritis (23), reflecting the broad importance of its biological role as an extracellular chaperone.…”

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

“…DMPS vesicles were prepared as previously reported (12) and aggregation kinetics and related data analysis were carried out as previously described (12). α-Synuclein oligomers were also prepared as described previously (23,24) and cell cytotoxicity assays were carried out as indicated (43). In vivo experiments were carried out by using a well-studied C. elegans model of PD (25).…”