Pyroglutamation of amyloid-x-42 (Ax-42) followed by A1-40 deposition underlies plaque polymorphism in progressing Alzheimers disease pathology

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.Funding Agencies|Leonard Wolfson Centre for Experimental Neurology; Reta Lila Weston Institute for Neurological Studies; Medical Research Council