Detection of Amyloid-beta aggregates in body fluids: a suitable method for early diagnosis of Alzheimer's disease?

Forschungszentrum Jülich, ISB-3, 52425 Jülich, Germany.
Current Alzheimer research (Impact Factor: 4.97). 07/2009; 6(3):285-9.
Source: PubMed

ABSTRACT Today, the most reliable diagnosis for Alzheimer's disease (AD) is the post mortem identification of amyloid plaques, consisting of the Amyloid-beta (Abeta) peptide, (and neurofibrillary tangles) in the brain of the patient. Great efforts are being made to identify reliable biomarkers for AD that are suitable for minimal invasive early diagnosis and prognosis of AD. During the past years, body fluids of AD patients were assayed for their content of total or soluble Abeta(1-40) or Abeta(1-42) concentrations using classical (ELISA) or non-classical (with additional signal amplification) read-out. Cerebrospinal fluid (CSF) concentrations of soluble Abeta(1-42) are reduced by 40 to 50 % in AD patients compared to age-matched healthy controls as confirmed in more than 30 studies, with both sensitivity and specificity exceeding 80 % in most of the studies. Thus, it was suggested that low levels of CSF Abeta(1-42) might be useful for preclinical diagnosis. Because the current average sensitivity of AD biomarker detection in the CSF is approximately 85 %, these assays do not offer a considerable increase in predictive value over existing algorithms based on neuropsychological and imaging modalities. Regarding the amyloid cascade hypothesis, Abeta oligomers and aggregates are directly involved in the pathogenic process. Therefore, presence of Abeta aggregates seem to be the most direct disease biomarker for AD and increasing effort is being made into the development of methods suitable for the detection of different Abeta aggregates in body fluids like CSF and plasma. We therefore give an overview of the current state of Abeta aggregate specific detection.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβ assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβ peptides. Specifically, we focused our attention on the heterogeneity of the CSF Aβ world discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aβ assemblies, and (3) communication modes for Aβ peptides and their microenvironment targets. Finally, we suggest that Aβ peptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function.
    BioMed Research International 08/2011; 2011:697036. DOI:10.1155/2011/697036 · 2.71 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid β (Abeta) peptides in their oligomeric form have been proposed as major toxic species in Alzheimer's disease (AD). There are a limited number of anti-Abeta antibodies specific to oligomeric forms of Abeta compared to the monomeric form, and accurate measurement of oligomeric forms in biological samples, cerebrospinal fluid (CSF), or brain extracts remains challenging. We introduce an oligomer-specific (in preference to monomers or fibrils) fluorescence assay based on a conformationally sensitive bis-pyrene-labeled peptide that contains amino acid residues 16-35 of the human amyloid beta protein (pronucleon peptide, PP). This peptide exhibits a shift in fluorescence emission from pyrene excimer to pyrene monomer emission resulting from a conformational change. Specific binding of PP to oligomeric forms of Abeta can be monitored in solution by a change in fluorescence spectrum as well as a change in pyrene monomer fluorescence anisotropy (or polarization). The mechanism of binding and its relation to anisotropy and fluorescence lifetime changes are discussed. The development of a simple, rapid, anisotropy assay for measurement of Abeta oligomers is important for further study of the oligomers' role in AD, and specific detection of oligomers in biological samples, such as cerebrospinal fluid.
    ACS Chemical Neuroscience 11/2012; 3(11):982-7. DOI:10.1021/cn3001262 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid-beta (Aβ) in Alzheimer's disease (AD) appeared to be a promising target for disease-modifying therapeutic strategies like passive immunotherapy with anti-Aβ monoclonal antibodies (mAbs). Biochemical markers in cerebrospinal fluid (CSF) include alterations of Aβ that allow the diagnosis of AD. Biomarker strategies, such as the levels of Aβ in CSF and plasma, currently play an important role in early clinical trials for AD. Indeed, these strategies have a relevant impact on the outcome of such studies, since the biomarkers are used to monitor the bioactivity of anti-Aβ mAbs. The clinical trials of Solanezumab were mainly based on the readout of Aβ levels in CSF and plasma, whereas those of Bapineuzumab were based on cognition; however, little is known about the mechanisms altering these biomarker levels, and no biomarker has yet been proven to be a successful predictor for AD therapy. In addition, the Aβ biomarkers allow for the determination of free and bound anti-Aβ mAb in order to monitor the available amount of bioactive drug and could give hints to the mechanism of action. In this review, we discuss clinical Aβ biomarker data and the latest regulatory strategies.
    Frontiers in Aging Neuroscience 01/2013; 5:25. DOI:10.3389/fnagi.2013.00025 · 2.84 Impact Factor