Pyroglutamate-modified amyloid -B amplifies cytotoxicity and induces prion-like properties in conventional amyloid-B

Nussbaum, Justin Michael, Department of Biology, University of Virginia
Bloom, George, Department of Biology, University of Virginia

Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of two distinct proteins, amyloid-13 (A13) and tau in the brain. While it was long believed that these large aggregates represent the primary toxic substance in AD, new evidence suggests that soluble oligomers of A13 and tau act in conjunction to induce neurodegeneration. In particular, N-terminally truncated (positions 3 or 11), pyroglutamylated forms of amyloid-13 (pEA13) have been recently implicated in the pathogenesis of AD. pEA13 species represent a small percentage of brain A13, but are strongly associated with AD. pEA13 oligomers have been found to be more toxic than conventional A13, and have been proposed as a key initiator of AD pathogenesis. This work demonstrates a mechanism by which pEA13 could serve that role. In order to investigate the biochemical effects that pEA13 has on conventional A13, experiments were conducted in which small amounts of pEA133-42 were mixed as monomers with A131-42 and allowed to oligomerize together. pEA133-42 was found to interact with excess A131-42 to form oligomers that are far more cytotoxic to primary neurons than oligomers of A131-42 alone. In addition, these toxic species do not affect neurons taken from mice that lack tau. When separated by size exclusion chromatography, solutions exposed to pEA133-42 are enriched in a highly toxic species that migrates as an apparent dimer or trimer. Remarkably, cytotoxic dimers/trimers formed from mixing pEAf$3-42 with excess A131-42 can seed equally active dimers/trimers through multiple serial dilutions ofpre-formed oligomers into fresh A131-42 monomers in the absence of additional pEAf$3-42. These results demonstrate that small amounts of pEAf$3-42 can cause templateinduced A131-42 misfolding, resulting in low-n oligomers that propogate by a prion-like mechanism, and that these oligomers act through tau to kill IIEUFOIIS.

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PHD (Doctor of Philosophy)
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