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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Acta+Neuropathol+Commun 2018 ; 6 (1): 131 Nephropedia Template TP
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In vivo induction of membrane damage by beta-amyloid peptide oligomers #MMPMID30497524
Julien C; Tomberlin C; Roberts CM; Akram A; Stein GH; Silverman MA; Link CD
Acta Neuropathol Commun 2018[Nov]; 6 (1): 131 PMID30497524show ga
Exposure to the beta-amyloid peptide (Abeta) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Abeta oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Abeta oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Abeta exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Abeta induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Abeta Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer's disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Abeta multimerization and thus the formation of potentially pore-forming oligomers. We propose that Abeta-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.