Reduced Influence of apoE on Aβ43 Aggregation and Reduced Vascular Aβ43 Toxicity as Compared with Aβ40 and Aβ42.

Abstract

The amyloid-β 43 (Aβ43) peptide has been shown to be abundantly expressed in Alzheimer's disease plaques, whereas only relatively low levels have been demonstrated in cerebral amyloid angiopathy (CAA). To better understand this discrepant distribution, we studied various biochemical properties of Aβ43, in comparison with Aβ40 and Aβ42. We assessed the interaction of Aβ43 with the three apoE isoforms (apoE2, apoE3, and apoE4) using SDS-PAGE/Western blotting and ELISA, aggregation propensity using thioflavin T assays, and cytotoxicity towards cerebrovascular cells using MTT assays. We found that Aβ43 did not differ from Aβ42 in its interaction with apoE, whereas Aβ40 had a significantly lower degree of interaction with apoE. At a molar ratio of 1:100 (apoE:Aβ), all apoE isoforms were comparably capable of inhibiting aggregation of Aβ40 and Aβ42, but not Aβ43. All Aβ variants had a concentration-dependent negative effect on metabolic activity of cerebrovascular cells. However, the degree of this effect differed for the three Aβ isoforms (Aβ40 > Aβ42 > Aβ43), with Aβ43 being the least cytotoxic peptide towards cerebrovascular cells. We conclude that Aβ43 has different biochemical characteristics compared with Aβ40 and Aβ42. Aggregation of Aβ43 is not inhibited by apoE, in contrast to the aggregation of Aβ40 and Aβ42. Furthermore, cerebrovascular cells are less sensitive towards Aβ43, compared with Aβ40 and Aβ42. In contrast, Aβ43 neither differed from Aβ42 in its aggregation propensity (in the absence of apoE) nor in its apoE-binding capacity. Altogether, our findings may provide an explanation for the lower levels of Aβ43 accumulation in cerebral vessel walls.

• Authors: Lieke Jäkel, Elisanne A L M Biemans, Catharina J M Klijn, H Bea Kuiperij, Marcel M Verbeek
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 57 Issue 4 Pg. 2131-2141 (Apr 2020) ISSN: 1559-1182 [Electronic] United States
• PMID: 31953617 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Amyloid beta-Peptides
• Apolipoproteins E
• Peptide Fragments
• Protein Aggregates
• Protein Isoforms
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• amyloid beta-protein (1-43)

Topics

• Amyloid beta-Peptides (toxicity)
• Apolipoproteins E (metabolism)
• Brain (blood supply, metabolism)
• Cells, Cultured
• Humans
• Kinetics
• Peptide Fragments (toxicity)
• Protein Aggregates (drug effects)
• Protein Isoforms (metabolism)