Extracellular chaperones prevent Aβ42-induced toxicity in rat brains

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Cascella, Roberta¹  Conti, Simona¹  Tatini, Francesca¹  Evangelisti, Elisa¹  Scartabelli, Tania²  Casamenti, Fiorella³  Wilson, Mark R.⁴  Chiti, Fabrizio^1,5  Cecchi, Cristina¹ 

[1] Univ Florence, Dept Biomed Expt & Clin Sci, I-50134 Florence, Italy

[2] Univ Florence, Dept Hlth Sci DSS, I-50139 Florence, Italy

[3] Univ Florence, Dept Neurosci Psychol Drug Area & Child Hlth, I-50139 Florence, Italy

[4] Univ Wollongong, Sch Biol Sci, Wollongong, NSW 2522, Australia

[5] INBB, Consorzio Interuniv, I-00136 Rome, Italy

关键词: Extracellular chaperone;    Amyloid neurotoxicity;    Hippocampal injury;    Learning impairment;    Memory injury;    A beta(42)/PSD-95 colocalisation;   

DOI  :  10.1016/j.bbadis.2013.04.012

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, formation of the extracellular amyloid beta (A beta(42)) 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 A beta oligomer toxicity remains unclear, with reports often appearing contradictory. In this study we microinjected into the hippocampus of rat brains A beta(42) oligomers pre-incubated for 1 h with two extracellular chaperones, namely clusterin and alpha(2)-macroglobulin. The chaperones were found to prevent A beta(42)-induced learning and memory impairments, as assessed by the Morris Water Maze test, and reduce A beta(42)-induced glia inflammation and neuronal degeneration in rat brains, as probed by fluorescent immunohistochemical analyses. Moreover, the chaperones were able to prevent A beta(42) 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 A beta(42) aggregation, as previously demonstrated, but also by suppressing the toxicity of A beta(42) 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. (C) 2013 Elsevier B.V. All rights reserved.

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