N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer's pathophysiology

Background: The molecular heterogeneity of Alzheimer's amyloid-beta (A beta) deposits extends well beyond the classic A beta 1-40/A beta 1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain A beta peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. A beta 4-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 A beta 4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6-specific for A beta 4-x species and blind for full-length A beta 1-40/A beta 1-42-in conjunction with thioflavin-S and antibodies recognizing A beta x-40 and A beta x-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 A beta epitopes, albeit expressed in different proportions. A beta 4-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 A beta 4-40 and A beta 4-42-consistently exhibited enhanced brain retention. Conclusions: The persistence of aggregation-prone A beta 4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.

Automated summary

This study found that Aβ4-x peptides are present in Alzheimer's amyloid-beta deposits and contribute to the formation of amyloid and the development of pathological pathways.