Refining the amyloid β peptide and oligomer fingerprint ambiguities in Alzheimer's disease: Mass spectrometric molecular characterization in brain, cerebrospinal fluid, blood, and plasma.

Michno W, Blennow K, Zetterberg H, Brinkmalm G

J. Neurochem. 159 (2) 234-257 [2021-10-00; online 2021-07-27]

Since its discovery, amyloid-β (Aβ) has been the principal target of investigation of in Alzheimer's disease (AD). Over the years however, no clear correlation was found between the Aβ plaque burden and location, and AD-associated neurodegeneration and cognitive decline. Instead, diagnostic potential of specific Aβ peptides and/or their ratio, was established. For instance, a selective reduction in the concentration of the aggregation-prone 42 amino acid-long Aβ peptide (Aβ42) in cerebrospinal fluid (CSF) was put forward as reflective of Aβ peptide aggregation in the brain. With time, Aβ oligomers-the proposed toxic Aβ intermediates-have emerged as potential drivers of synaptic dysfunction and neurodegeneration in the disease process. Oligomers are commonly agreed upon to come in different shapes and sizes, and are very poorly characterized when it comes to their composition and their "toxic" properties. The concept of structural polymorphism-a diversity in conformational organization of amyloid aggregates-that depends on the Aβ peptide backbone, makes the characterization of Aβ aggregates and their role in AD progression challenging. In this review, we revisit the history of Aβ discovery and initial characterization and highlight the crucial role mass spectrometry (MS) has played in this process. We critically review the common knowledge gaps in the molecular identity of the Aβ peptide, and how MS is aiding the characterization of higher order Aβ assemblies. Finally, we go on to present recent advances in MS approaches for characterization of Aβ as single peptides and oligomers, and convey our optimism, as to how MS holds a promise for paving the way for progress toward a more comprehensive understanding of Aβ in AD research.

SciLifeLab Fellow

Wojciech Michno

PubMed 34245565

DOI 10.1111/jnc.15466

Crossref 10.1111/jnc.15466

Publications 9.5.0