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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.

Artikel i vetenskaplig tidskrift
Författare Wojciech Michno
Sofie Nyström
Patrick M. Wehrli
Tammaryn Lashley
Gunnar Brinkmalm
Laurent Guerard
Stina Syvänen
Dag Sehlin
Ibrahim Kaya
Dimitri Brinet
K Peter R Nilsson
Per Hammarström
Kaj Blennow
Henrik Zetterberg
Jörg Hanrieder
Publicerad i Journal of Biological Chemistry
Volym 294
Nummer/häfte 17
Sidor 6719-6732
ISSN 0021-9258
Publiceringsår 2019
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Core Facilities, Centre for Cellular Imaging
Sidor 6719-6732
Språk en
Länkar dx.doi.org/10.1074/jbc.RA118.006604
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Neurovetenskaper

Sammanfattning

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 that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of Aβ1-42 and that Aβ plaque maturation over time is associated with increases in Aβ1-40. Finally, we found that Aβ1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Aβx-42 pyroglutamation and Aβ1-40 deposition are critical events in priming and maturation of pathogenic Aβ from diffuse into cored plaques, underlying neurotoxic plaque development in AD.

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Denna text är utskriven från följande webbsida:
http://gu.se/forskning/publikation/?publicationId=287077
Utskriftsdatum: 2020-05-27