Dataset Information

Reduced Influence of apoE on A?43 Aggregation and Reduced Vascular A?43 Toxicity as Compared with A?40 and A?42.

ABSTRACT: The amyloid-? 43 (A?43) 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 A?43, in comparison with A?40 and A?42. We assessed the interaction of A?43 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 A?43 did not differ from A?42 in its interaction with apoE, whereas A?40 had a significantly lower degree of interaction with apoE. At a molar ratio of 1:100 (apoE:A?), all apoE isoforms were comparably capable of inhibiting aggregation of A?40 and A?42, but not A?43. All A? variants had a concentration-dependent negative effect on metabolic activity of cerebrovascular cells. However, the degree of this effect differed for the three A? isoforms (A?40?>?A?42?>?A?43), with A?43 being the least cytotoxic peptide towards cerebrovascular cells. We conclude that A?43 has different biochemical characteristics compared with A?40 and A?42. Aggregation of A?43 is not inhibited by apoE, in contrast to the aggregation of A?40 and A?42. Furthermore, cerebrovascular cells are less sensitive towards A?43, compared with A?40 and A?42. In contrast, A?43 neither differed from A?42 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 A?43 accumulation in cerebral vessel walls.

SUBMITTER: Jakel L

PROVIDER: S-EPMC7118029 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Jäkel Lieke L Biemans Elisanne A L M EALM Klijn Catharina J M CJM Kuiperij H Bea HB Verbeek Marcel M MM

Molecular neurobiology 20200117 4

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 ...[more]

PMID: 31953617

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Project description:Background: Amyloid beta 1-43 (A?43) may be a useful additional biomarker for diagnosing Alzheimer's disease (AD). We have investigated cerebrospinal fluid (CSF) levels of A?43 in patients with early-onset AD in contrast to levels in late-onset AD. For comparison, in addition to the 'core' biomarkers, several other analytes were also determined [YKL-40, neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), and progranulin]. Material and Methods: Cerebrospinal fluid samples were obtained from patients with early-onset AD (age ? 62, n = 66), late-onset AD (age ? 68, n = 25), and groups of cognitively intact individuals (age ? 62, n = 41, age ? 68, n = 39). Core CSF AD biomarkers [amyloid beta 1-42 (A?42), total tau, phosphorylated tau] were analyzed, as well as levels of A?43 and other analytes, using commercially available enzyme-linked immunosorbent assays. Results: Cerebrospinal fluid A?43 was significantly reduced in early-onset AD compared to late-onset AD (14.8 ± 7.3 vs. 21.8 ± 9.4 pg/ml, respectively), whereas the levels of A?42 in the two AD groups were not significantly different (474.9 ± 142.0 vs. 539.6 ± 159.9 pg/ml, respectively). A?43 and all core biomarkers were significantly altered in patients with AD compared to corresponding controls. NF-L was significantly increased in early-onset AD compared to younger controls, an effect not found between the older groups. Relationships between the A? peptides and tau proteins, YKL-40, NF-L, GFAP and progranulin were also investigated without finding marked associations. However, age-associated increases in levels of tau proteins, YKL-40, NF-L and GFAP were found with respect to age in healthy controls. Results for these other analytes were similar to previously published data. A?43 did not improve diagnostic accuracy in either AD group compared to A?42.DiscussionCerebrospinal fluid A?43, but not A?42 levels, varied significantly with age in patients with AD. If CSF levels of A? peptides reflect amyloid deposition in brain, the possibility arises that there is a difference between A?43 and A?42 deposition in younger compared to older brain. However, the level of A?43 in CSF shows no improvement over A?42 regarding diagnostic accuracy.

Dataset Information

Reduced Influence of apoE on A?43 Aggregation and Reduced Vascular A?43 Toxicity as Compared with A?40 and A?42.

Publications

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

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