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  • Title: In vivo localization of human acetylcholinesterase-derived species in a β-sheet conformation at the core of senile plaques in Alzheimer's disease.
    Author: Jean L, Brimijoin S, Vaux DJ.
    Journal: J Biol Chem; 2019 Apr 19; 294(16):6253-6272. PubMed ID: 30787102.
    Abstract:
    Many neurodegenerative diseases are characterized by amyloid deposition. In Alzheimer's disease (AD), β-amyloid (Aβ) peptides accumulate extracellularly in senile plaques. The AD amyloid cascade hypothesis proposes that Aβ production or reduced clearance leads to toxicity. In contrast, the cholinergic hypothesis argues for a specific pathology of brain cholinergic pathways. However, neither hypothesis in isolation explains the pattern of AD pathogenesis. Evidence suggests that a connection exists between these two scenarios: the synaptic form of human acetylcholinesterase (hAChE-S) associates with plaques in AD brains; among hAChE variants, only hAChE-S enhances Aβ fibrillization in vitro and Aβ deposition and toxicity in vivo Only hAChE-S contains an amphiphilic C-terminal domain (T40, AChE575-614), with AChE586-599 homologous to Aβ and forming amyloid fibrils, which implicates T40 in AD pathology. We previously showed that the amyloid scavenger, insulin-degrading enzyme (IDE), generates T40-derived amyloidogenic species that, as a peptide mixture, seed Aβ fibrillization. Here, we characterized 11 peptides from a T40-IDE digest for β-sheet conformation, surfactant activity, fibrillization, and seeding capability. We identified residues important for amyloidogenicity and raised polyclonal antibodies against the most amyloidogenic peptide. These new antisera, alongside other specific antibodies, labeled sections from control, hAChE-S, hAPPswe, and hAChE-S/hAPPswe transgenic mice. We observed that hAChE-S β-sheet species co-localized with Aβ in mature plaque cores, surrounded by hAChE-S α-helical species. This observation provides the first in vivo evidence of the conformation of hAChE-S species within plaques. Our results may explain the role of hAChE-S in Aβ deposition and aggregation, as amyloidogenic hAChE-S β-sheet species might seed Aβ aggregation.
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