Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology
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
References
The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation
Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.
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