Abstract
Exposure to the β-amyloid peptide (Aβ) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Aβ oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Aβ oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Aβ 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 Aβ 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 Aβ 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 Aβ multimerization and thus the formation of potentially pore-forming oligomers. We propose that Aβ-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.
Highlights
Alzheimer’s disease is characterized by the deposition in the brain of senile plaques, composed largely of the β-amyloid peptide (Aβ)
Aβ induces a membrane repair process in C. elegans To assay the ability of human Aβ to induce membrane repair in an in vivo model, we took advantage of previous work by Aroian and colleagues, who studied the effects of the CRY5B toxin on C. elegans [31, 38, 85]
This induction of endocytosis was not observed in KWN117 worms exposed to an E. coli strain expressing the Gly37Leu variant of Aβ, which we have previously shown to be non-toxic in mammalian neurons [20]. (The engineered E. coli strain expressing the Aβ42 Gly37Leu variant produces higher levels of Aβ peptide than the Aβ42 wild type strain when assayed by immunoblot, Additional file 1: Figure S1C)
Summary
Alzheimer’s disease is characterized by the deposition in the brain of senile plaques, composed largely of the β-amyloid peptide (Aβ). While there is still significant controversy as to whether the amyloid cascade hypothesis explains Alzheimer’s pathology [28, 39, 72], there is extensive evidence (in vitro and in vivo) that exposure of neurons to Aβ can lead to tau hyperphosphorylation, a potential driver. Aβ toxicity in numerous models can be attenuated by blocking the NMDA-type glutamate receptor [5, 11, 24], suggesting that this calcium channel could be responsible for Aβ-dependent calcium influx. While multiple calcium channels could be involved in Aβ-dependent calcium influx, other studies suggest that Aβ oligomers could act independently of endogenous calcium channels by directly forming a calcium-permeable pore. Ring-like structures of Aβ oligomers have been visualized by atomic force microscopy in synthetic membranes [46], Aβ membrane pores in pathologically-relevant cells have not been directly visualized or assayed
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