Aminoterminally Truncated and Oxidized Amyloid-β Peptides in the Cerebrospinal Fluid of Alzheimer's Disease Patients

Abstract

Carboxyterminally elongated and aminoterminally truncated amyloid-β (Aβ) peptides and their oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to clarify the diagnostic impact of the Aβ peptides 1-38ox, 2-40, and 2-42 peptides on the neurochemical cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD). For this purpose, 22 patients with AD and 20 non-demented disease controls (NDC) were comparatively analyzed for their cerebrospinal fluid pattern of Aβ1-38ox, Aβ2-40, and Aβ2-42 along with Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-40ox, and Aβ1-42 using a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and subsequent analysis in the Aβ-SDS-PAGE/immunoblot. The Aβ peptides 1-38ox, 2-40, and 2-42 could not be consistently detected in the investigated CSF samples, which applied to samples from AD and NDC patients alike. Otherwise, our approach revealed a striking decrease of Aβ1-42 and Aβ2-42, but not of Aβ1-38ox and Aβ2-40 in AD. Both Aβ1-42 and Aβ2-42 reached reasonable accuracies for diagnosing AD alone as well as in relation to Aβ1-40, Aβ1-38, or the sum of all measured Aβ peptides. Aβ1-38ox was negatively correlated to the Mini-Mental Status Examination score of AD patients, indicating that this peptide to linked to disease severity. We conclude that an exact analysis of CSF Aβ peptides regarding their carboxy- and aminoterminus as well as posttranslational modification may be a promising approach for diagnosing and tracking AD.

Elucidation of Amyloid-Beta’s Gambit in Oligomerization: Truncated Aβ fragments of residues Aβ1-23, Aβ1-24 and Aβ1-25 rapidly seed to form SDS-stable, LMW Aβ oligomers that impair synaptic plasticity

“…Generally, our findings allow to draw strong parallels with earlier reported observations of typical Aβ fragment fingerprints (12) as well as the detection of a repertoire of different Nand, C-terminally truncated Aβ species in human CSF samples (36,49,50). The independent report of specific Aβ fragments found in human post-mortem AD brains as well as Downsyndrome (DS) subjects (51,52) further corroborates the significance of the findings reported here.…”

“…Our unbiased MS identification of identical Aβ fragment fingerprints, together with the JD1 positive assemblies detected in post-mortem AD brains, further highlights the pathological significance of Aβ fragments; Aβ1-23 to Aβ1-25. Generally, our findings allow to draw strong parallels with earlier reported observations of typical Aβ fragment fingerprints (12) as well as the detection of a repertoire of different N- and, C-terminally truncated Aβ species in human CSF samples (36,49,50). The independent report of specific Aβ fragments found in human post-mortem AD brains as well as Down- syndrome (DS) subjects (51, 52) further corroborates the significance of the findings reported here.…”

The Potential of Pathological Protein Fragmentation in Blood-Based Biomarker Development for Dementia – With Emphasis on Alzheimer’s Disease

“…The peptides are generated by N- or C-terminal truncation of Aβ and several of these have been identified in CSF, e.g., Aβ n –42 ( n = 2–11), Aβ 1– n ( n = 13–20), Aβ 1–28 , Aβ 1–33 , Aβ 1–34 , and Aβ 1– n ( n = 37–39). These peptides have been found to be elevated in CSF of AD patients but only few are involved in plaque formation ( 86 – 89 ).…”