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.

Role of adipocyte Na,K-ATPase oxidant amplification loop in cognitive decline and neurodegeneration

“…Doxycycline induced adipocyte specific NaKtide expression in these WD fed mice significantly attenuated the Iba1-positive microglia in the hippocampus ( Figure S3 ). These findings were consistent with the plasma levels of amyloid beta-40 (Aβ-40), a marker of cognitive decline ( Jakel et al., 2020 ; Rosu et al., 2020 ; Tsai et al., 2021 ; Watt et al., 2020 ), which showed significant increases in the WD fed mice ( Figure 3 F). The increase in Aβ-40 levels was significantly attenuated by doxycycline induced NaKtide expression ( Figure 3 F).…”

Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

“…Unfortunately, age at onset, gender and APOE genotype could not be used as covariates in the analysis, because the number of mutation carriers was not sufficient for the statistical test. Our pilot study is nevertheless relevant because it highlights the involvement of Aβ 1-43 in AD and adds missing information regarding specific mutations to very recent studies published during these last 2 years [23,25,48]. As CSF Aβ 1-43 has never been studied before in CSF of APP and PSENs mutation carriers, the results need to be interpreted with caution and more studies are needed to replicate these findings in larger cohorts.…”

“…2; Table 2). However, a recent study showed a reduced influence of APOE on Aβ 1-43 aggregation in cerebrovascular cells [48].…”

“…The production of longer Aβ peptides (> Aβ 1-42 ), including Aβ 1-43 , in the pathogenesis of AD is receiving increased attention [23,25,26,29,48]. Studies showed that the PSEN1 p.L435F produces primarily Aβ 1-43 , which was detected in the brain plaques [49] and induced pluripotent stem cell (iPSC) neurons [50] of patients carrying this mutation.…”

Illuminating amyloid fibrils: Fluorescence-based single-molecule approaches

“…Moreover, the use of ALEX-FCCS and FCS in this work highlights how single-molecule fluorescence techniques can be used to uncover molecular mechanisms that relate to the onset and progression of diseases associated with amyloid fibril formation. Elucidating the details of these dynamic biomolecular associations is not possible using post-mortem tissues from patients [207] , [208] .…”