Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology

The Journal of Biological Chemistry
Wojciech MichnoJörg Hanrieder

Abstract

Amyloid-β (Aβ) pathology in Alzheimer's disease (AD) is characterized by the formation of polymorphic deposits comprising diffuse and cored plaques. Because diffuse plaques are predominantly observed in cognitively unaffected, amyloid-positive (CU-AP) individuals, pathogenic conversion into cored plaques appears to be critical to AD pathogenesis. Herein, we identified the distinct Aβ species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated Aβ polymorphism with amyloid conformation-sensitive dyes and a novel in situ MS paradigm for chemical characterization of hyperspectrally delineated plaque morphotypes. We found that maturation of diffuse into cored plaques correlated with increased Aβ1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that Aβ1-40 aggregates at the core structure of mature plaques, whereas Aβ1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Aβx-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating Aβ1-40 deposition. Experiments in tgAPPSwe mice verified...Continue Reading

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Citations

Jul 28, 2020·Journal of Alzheimer's Disease : JAD·Gemma LombardiSandro Sorbi
Jun 11, 2021·Current Neurology and Neuroscience Reports·Boris DecourtMarwan Noel Sabbagh
Jun 9, 2021·Chembiochem : a European Journal of Chemical Biology·Therése KlingstedtK Peter R Nilsson
Sep 3, 2021·Journal of Neurochemistry·Eleni GkanatsiouGunnar Brinkmalm
Sep 15, 2021·ACS Chemical Neuroscience·Soumya MukherjeeColin L Masters

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Methods Mentioned

BETA
imaging techniques
transgenic
immunoprecipitation
fluorescence microscopy
fluorescence imaging
transgenics

Software Mentioned

Origin
Flex Imaging
FlexAnalysis
PEAKS Studio
Mascot Distiller
ImageJ
R script
GraphPad Prism
Zen
Matrix Science

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