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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.

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 tgAPP_Swe 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.

SUBMITTER: Michno W

PROVIDER: S-EPMC6497931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods We included individuals with a positive (n?=?176: 63?±?7?years, 87 (49%) females) or negative (n?=?76: 61?±?9?years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET?), mild cognitive impairment (26 PET+, 24 PET?), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p?=?0.009 and p?<?0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p?=?0.001 and p?=?0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC?=?88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized ? (s?)?=???0.40 to ??0.26; NfL: range s??=???0.35 to ??0.18; all: p?<?0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range s??=?0.22 – 0.11; all: p?<?0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman’s rho>?0.33, p?<?0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman’s rho?=???0.24, p?=?0.001). Discussion and conclusions Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.

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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.

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