| First Author | Michno W | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 17 | Pages | 6719-6732 |
| PubMed ID | 30814252 | Mgi Jnum | J:278232 |
| Mgi Id | MGI:6324134 | Doi | 10.1074/jbc.RA118.006604 |
| Citation | Michno W, et al. (2019) Pyroglutamation of amyloid-betax-42 (Abetax-42) followed by Abeta1-40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology. J Biol Chem 294(17):6719-6732 |
| abstractText | Amyloid-beta (Abeta) 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 Abeta species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated Abeta 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 Abeta1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that Abeta1-40 aggregates at the core structure of mature plaques, whereas Abeta1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Abetax-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating Abeta1-40 deposition. Experiments in tgAPPSwe mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of Abeta1-42 and that Abeta plaque maturation over time is associated with increases in Abeta1-40. Finally, we found that Abeta1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Abetax-42 pyroglutamation and Abeta1-40 deposition are critical events in priming and maturation of pathogenic Abeta from diffuse into cored plaques, underlying neurotoxic plaque development in AD. |
