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Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1–40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology
Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.
Linkoping Univ, Dept Phys Chem & Biol, S-58183 Linkoping, Sweden.
Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.
UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London WC1N 3BG, England.
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 17, p. 6719-6732Article in journal (Refereed) Published
Abstract [en]

Amyloid- (A) 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 A species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated A 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 A1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that A1-40 aggregates at the core structure of mature plaques, whereas A1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Ax-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating A1-40 deposition. Experiments in tgAPP(Swe) mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of A1-42 and that A plaque maturation over time is associated with increases in A1-40. Finally, we found that A1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Ax-42 pyroglutamation and A1-40 deposition are critical events in priming and maturation of pathogenic A from diffuse into cored plaques, underlying neurotoxic plaque development in AD.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2019. Vol. 294, no 17, p. 6719-6732
Keywords [en]
amyloid-beta (A), Alzheimer disease, mass spectrometry (MS), imaging, protein aggregation, neurodegeneration, pyroglutamation, plaque polymorphism, hyperspectral imaging, transgenic mice, pyroglutamic acid
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-383851DOI: 10.1074/jbc.RA118.006604ISI: 000467394700011PubMedID: 30814252OAI: oai:DiVA.org:uu-383851DiVA, id: diva2:1317979
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-05-24Bibliographically approved

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