title: 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.
authors.affiliation: Department of Biomedical Experimental and Clinical Sciences, University of Florence, V.le GB Morgagni 50, 50134, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.forename: Simona
authors.initials: S
authors.lastname: Conti
authors.forename: Francesca
authors.initials: F
authors.lastname: Tatini
authors.forename: Elisa
authors.initials: E
authors.lastname: Evangelisti
authors.forename: Tania
authors.initials: T
authors.lastname: Scartabelli
authors.forename: Fiorella
authors.initials: F
authors.lastname: Casamenti
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.forename: Cristina
authors.initials: C
authors.lastname: Cecchi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007859:Learning Disabilities / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D010446:Peptide Fragments; D000511:alpha-Macroglobulins; C075222:amyloid beta-protein (1-42)