Quantitative detection of amyloid-β peptides by mass spectrometry: state of the art and clinical applications

Abstract

Alzheimer's disease (AD) is the most common form of dementia in humans, and a major public health concern with 35 million of patients worldwide. Cerebrospinal fluid (CSF) biomarkers being early diagnostic indicators of AD, it is essential to use the most efficient analytical methods to detect and quantify them accurately. These biomarkers, and more specifically amyloid-β (Aβ) peptides, are measured in routine clinical practice using immunoassays. However, there are several limits to this immunodetection in terms of specificity and multiplexing of the multiple isoforms of the Aβ peptides. To overcome these issues, the quantification of these analytes by mass spectrometry (MS) represents an interesting alternative, and several assays have been described over the past years. This article reviews the different Aβ peptides quantitative MS-based approaches published so far, compares their pre-analytical phase, and the different quantitative strategies implemented that might be suitable for clinical applications.

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…1d). Due to the differential ionization properties of similar peptides, the quantitative analysis of MALDI-TOF measurements is limited and the peak heights in the mass spectra do not correspond to the abundance of individual peptides [9]. To obtain quantitative data and to confirm these results with an independent method, culture supernatants were analyzed with a sandwich ELISA that combined an Aβ40 C-terminus-specific antibody with the polyclonal antibody 029-2, which exclusively detects Aβ4-x peptides with Phe at position 4, as described [79].…”

Computational integration of nanoscale physical biomarkers and cognitive assessments for Alzheimer’s disease diagnosis and prognosis

“…Studies have also been conducted with peptide self-assembly that relate structures to molecular activities and mechanical properties ( 27 ). Because pathological protein components inside the cerebral spinal fluid (CSF) and blood undergo macro- to nanolevel physical changes that promote physiological changes, such as the formation of protein aggregates that reflect disease advancement ( 28 ), these components and their physical changes during the aggregation may be detectable through nanoscale characterization and may have the potential to be used as a new class of “physical biomarkers” for AD diagnosis. This may provide a potential measure to determine how alterations to the nanomechanics and nanomorphology of proteins in patients’ CSF and blood reflect and affect AD onset and pathogenesis.…”

Mass spectrometry analysis of the diversity of Aβ peptides: difficulties and future perspectives for AD biomarker discovery

“…Besides this, due to the invasive nature of CSF sampling, blood plasma seems to be a more attractive subject for analysis; however, it requires the enrichment step even more. Currently, immunoprecipitation (IP), mild cation-exchange solid-phase extraction, and molecularly imprinted polymers have been used for this purpose [10,11]. The listed methods still have a number of limitations and do not guarantee the complete isolation of the diversity of Aβ peptides.…”

“…At the same time, the significant (~85%) prevalence of modified and Nand C-terminal truncated Aβ peptides in AD brains [9], strongly suggests that some of these Aβ-forms may be more specific and reliable as early AD risk markers. And, many of the C-terminal truncated and modified Aβ-forms were even observed by MS in CSF and plasma, though their clinical importance still remains to be elucidated [11], as their content in brain is quite different ( Table 1). However, the N-terminal truncated forms, which are prevalent in the brain, may be more appropriate candidates for early AD biomarkers in CSF or plasma and may represent a good perspective for further investigations.…”