Elsevier

Analytica Chimica Acta

Volume 940, 12 October 2016, Pages 21-37
Analytica Chimica Acta

Review
Detecting Alzheimer's disease biomarkers: From antibodies to new bio-mimetic receptors and their application to established and emerging bioanalytical platforms – A critical review

https://doi.org/10.1016/j.aca.2016.08.008Get rights and content

Highlights

  • Alzheimer's biomarkers detection on conventional and innovative platforms are reviewed.

  • Analytical performances in detecting amyloid-β and Tau protein species are reported.

  • Critical aspects related to inter-laboratory variability of results are discussed.

  • Emerging synthetic receptors for AD biomarkers detection are presented and compared.

  • Future outlooks on alternative matrices and AD biomarkers are presented.

Abstract

The failure of therapeutic treatment of Alzheimer's disease (AD) patients can be related to the late onset of symptoms and, consequently, to a delayed pharmacological aid to counteract neurodegenerative progression. This is coupled to the fact that the diagnosis based on clinical criteria alone introduces high misdiagnosis rate. The availability of assessed biomarkers is therefore of crucial importance not only to counteract late diagnosis, but also to manage patients at high risk of AD development eligible for novel therapies. At the present time, amyloid-β peptides (Aβ1-40 and Aβ1-42 isoforms), alone or in combination with Tau protein (total and phosphorylated forms (p-tau)) constitute reliable AD biomarkers and result highly predictive of progression to AD dementia in patients with mild cognitive impairment (MCI), the earliest clinical presentation of AD. Improvement of existing diagnostic tools must take advantage of innovative bioanalytical approaches. In this review, starting from commercially available diagnostic platforms based on antibodies as recognition elements, we intended to provide a double point of view on the issue: 1) progresses achieved on innovative bioanalytical platforms (mainly sensors and biosensors) by using antibodies as consolidated receptors; 2) advance on promising bio-mimetic receptors alternative to antibodies in AD research, and their applications on conventional or innovative analytical platforms. In particular, we first focused on optical- (Propagating and Localized Surface Plasmon Resonance, named here SPR and LSPR) and electrochemical (voltammetric and impedimetric) transduction principles. Together with bioanalytical assays for AD biomarkers quantification, works aimed to investigate and understand their behavior, characteristics, and roles will also be considered in the discussion.

An increasing interest in new emerging biomimetic receptors for AD diagnosis, as a promising alternative to antibodies is noticed, thus the description of peptides, peptoids, nanobodies, aptamers, and molecularly imprinted polymers and their role as recognition elements in different bioanalytical platforms is also reviewed. Features and limits are discussed, together with potentialities and perspectives of their further applicability to clinical routine AD analysis.

Section snippets

Generalities of Alzheimer's disease

Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907 as a severe neurodegenerative disorder characterized by progressive memory and cognitive impairment, with evolution to dementia and death observed on a 50-year-old woman [1], [2]. Brain histologies related to this new clinical condition presented two main hallmarks, i.e. distinctive plaques and neurofibrillary tangles (NFTs) whose composition was clarified only in the eighties with the discovery of the amyloid beta peptide

Overview on consolidated AD biomarkers

Nowadays, three core biomarkers are considered for routine diagnosis of AD in cerebrospinal fluid (CSF): amyloid beta peptides (Aβ1-42 and Aβ1-40), total tau protein (t-τ), and tau protein phosphorylated on threonine 181 (p-tau181). Such markers are involved in the well-known amyloid cascade hypothesis, which has been the basis of research in the field for the last 20 years [9], [10], (sketched in Fig. 1). This milestone puts tau aggregation downstream to amyloid deposits; however, tau

Immuno-based platforms on the market: ELISA and xMAP® assays

At the present time, the most widely used immunoassay platforms for CSF AD biomarkers detection (Aβ peptides 1–40 and 1–42, total tau (6 isoforms), and p-tau181) are provided by Fujirebio-Innogenetics (Innogenetics Inc., Alpharetta, GA) and consist in a singleplex enzyme-linked immunosorbent assay (ELISA) kit and a micro-bead based Multi-Analyte Profile (xMAP®) (also recently reviewed by Kang and colleagues [36]). The bioanalytical strategy of the two immunoassays benefits from the development

Propagating Surface Plasmon Resonance (SPR)

Several biosensors, based on various transduction principles, are reported in literature for AD biomarkers detection, whose performances have also been critically reviewed [44], [45]. Label free optical techniques, such as Surface Plasmon Resonance (SPR, conventional and imaging) [46], [47], [48], or Localized SPR (LSPR) [49], as well as electrochemical techniques, offer the possibility to detect biomolecular interactions with high sensitivity, and in real time. In Table 2, an overview of these

Biomimetic receptors as alternative to immunodetection

In the last decades, great efforts have been directed toward the design and the selection of innovative synthetic receptors that may realize the dream of effective alternatives to classical antibodies. At present, several classes of synthetic receptors have been widely tested at research level and are now also available on the market. Biomimetic receptors share with their natural counterpart the unique feature of recognizing their target analytes in a specific and selective manner, being at the

Conclusions and future outlooks

This review provides a critical viewpoint on bioanalytical approaches to CSF AD biomarkers detection, moving from conventional assays based on antibodies as bioreceptors (ELISA and xMAP®) toward innovative approaches both in terms of bioanalytical platforms and synthetic receptors. Conventional methods are still the best choice for routine diagnosis, while more likely emerging techniques are going to play a role in the study of marker levels variability and aggregation patterns. Among currently

Acknowledgments

The authors would like to thank the Università Italo-Francese, Bando “Leonardo da Vinci” 2013, Three-years PhD scholarships in cotutela, chapter 3, title of the research: “Sviluppo di Biosensori di affinità a base di un nuovo recettore aptamerico, per la diagnostica molecolare della malattia di Alzheimer” for financial support. S. S. and M. M. thank the Ministry of Education, University and Research (MIUR) for the scientific program SIR2014 Scientific Independence of young Researchers (

Simona Scarano received her M.Sc. Degree in chemistry in 2002 (University of Pisa, Italy), then spent three years as researcher at Gnosis S.p.a., (Milan, Italy) as researcher. She joined the 'Sensors and Biosensors' laboratory in 2007, where she received her Ph.D in 2011. At present she has a researcher position, working on affinity-based biosensors for clinical diagnostics, anti-doping, and cultural heritage conservation. She coordinates the 'Scientific Independence of young Researchers'

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  • Cited by (0)

    Simona Scarano received her M.Sc. Degree in chemistry in 2002 (University of Pisa, Italy), then spent three years as researcher at Gnosis S.p.a., (Milan, Italy) as researcher. She joined the 'Sensors and Biosensors' laboratory in 2007, where she received her Ph.D in 2011. At present she has a researcher position, working on affinity-based biosensors for clinical diagnostics, anti-doping, and cultural heritage conservation. She coordinates the 'Scientific Independence of young Researchers' project funded by Italian Ministry for Education, University and Research for the development of point-of-care nanosensors based on new synthetic bioreceptors coupled to localized SPR detection for clinical diagnostics.

    Samuele Lisi is a PhD student at University of Florence, Italy in cotutela with University of Grenoble Alpes, France, within the Project funded by Università Italo-Francese, Bando “Leonardo da Vinci” 2013, Borse triennali di dottorato in cotutela, capitolo 3; Title of the research: “Sviluppo di Biosensori di affinità a base di un nuovo recettore aptamerico, per la diagnostica molecolare della malattia di Alzheimer”.

    Corinne Ravelet is assistant professor since 2003 at the Grenoble Alpes University (France) in the Pr. Eric Peyrin's team. In the 2000s, her work in the Molecular Pharmacochemistry's Department focused on chiral discrimination and the use of the enantioselective properties of the aptamers. Since the 2010s, her researches are mainly centered on the development of diagnosis tools based on the molecular recognition properties of aptamers. As a specialist in analytical chemistry and capillary electrophoresis, she is in charge of the development of aptamers against bioactive targets through Capillary Electrophoresis-SELEX.

    Eric Peyrin is Professor of Analytical Chemistry at the Grenoble Alpes University (France) since 2001. His research activities focus on the development of analytical tools based on the molecular recognition properties of bioelements such as functional nucleic acids, in particular the study of chiral recognition mechanisms and for application to the enantioselective sensing in the biological, pharmaceutical and environmental fields. He received in 2010 the prize of the French chemical society, is associate editor of the “Frontiers in Chemistry” journal, and has been guest editor in 2016 for a special issue dedicated to Nucleic acid Aptamers in the “Methods” journal.

    Maria Minunni is Associate Professor of Analytical Chemistry (University of Florence, Italy). Since 1990 she is involved in biosensors research by different transduction principles, in particular piezoelectric, optical, and electrochemical. Her research activity covered mainly the development of affinity-based sensing (ABBs): immuno-, nucleic acid-, and aptamer-based sensors with different applications, from environmental, food, pharmaceutical analysis, to clinical diagnostic and, more recently, anti-doping analysis. She has funded by international and national Grants from Public institutions as coordinator or PI: European Union (FP7 and Horizon2020), World Antidoping Agency (WADA), Italian Ministy of Health; Regione Toscana; Università Italo-Francese, Bando “Leonardo da Vinci” 2013.

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