N-terminally truncated Aß4-x proteoforms and their relevance for Alzheimer's pathophysiology.
Transl Neurodegener
; 11(1): 30, 2022 06 01.
Article
em En
| MEDLINE
| ID: mdl-35641972
ABSTRACT
BACKGROUND:
The molecular heterogeneity of Alzheimer's amyloid-ß (Aß) deposits extends well beyond the classic Aß1-40/Aß1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aß peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aß4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer's disease (AD).METHODS:
Immunohistochemistry was used to assess the topographic distribution of Aß4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6-specific for Aß4-x species and blind for full-length Aß1-40/Aß1-42-in conjunction with thioflavin-S and antibodies recognizing Aßx-40 and Aßx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics.RESULTS:
All types of amyloid deposits contained the probed Aß epitopes, albeit expressed in different proportions. Aß4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts-particularly of Aß4-40 and Aß4-42-consistently exhibited enhanced brain retention.CONCLUSIONS:
The persistence of aggregation-prone Aß4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Alzheimer
Limite:
Animals
Idioma:
En
Revista:
Transl Neurodegener
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos