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Abstract
Despite extensive efforts on probing the mechanism of Alzheimer’s disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets. Herein, we focus on the chiral effects of truncated amyloid beta (Aβ) and offer further structural and molecular evidence for epitope region-specific, chirality-regulated Aβ fragment self-assembly and its potential impact on receptor-recognition. A multidimensional ion mobility-mass spectrometry (IM-MS) analytical platform and in-solution kinetics analysis reveal the comprehensive structural and molecular basis for differential Aβ fragment chiral chemistry, including the differential and cooperative roles of chiral Aβ N-terminal and C-terminal fragments in receptor recognition. Our method is applicable to many other systems and the results may shed light on the potential development of novel AD therapeutic strategies based on targeting the D-isomerized Aβ, rather than natural L-Aβ.
Highlights
Despite extensive efforts on probing the mechanism of Alzheimer’s disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets
Facing the analytical challenges and limitations, we aim to develop an integrated analytical platform, integrative chirality anatomy platform (iCAP), based on multidimensional IMMS measurements to simultaneously provide molecular and structural insights into the chiral chemistry of Aβ fragment selfassembly/oligomerization and its receptor recognition
In addition to the versatile compatibility with any other ion mobility-mass spectrometry (IM-MS) instruments and broad applicability to the study of other protein aggregation systems, iCAP can simultaneously address three challenges: [1] Rapidly and efficiently distinguish D/L-amino acid containing Aβ fragment monomers through metal-enhanced multidimensional epimeric discrimination (Fig. 1a); [2] Directly read out the Aβ fragment oligomerization processes using growth curves and evaluate the chiral effect involved in the oligomerization process (Fig. 1b); [3] Reliably visualize the chiral recognition-induced structural changes of receptors based on collision-induced unfolding (CIU)-IM-MS measurements and surface plasmon resonance (SPR)-based kinetic analysis (Fig. 1c)
Summary
Despite extensive efforts on probing the mechanism of Alzheimer’s disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets. Only a small portion (e.g., less than 10%) of Aβ species was found to be D-isomerized6 This fact along with the subtle structural changes induced by amino acid chiral inversion would lead to overlooking this important modification and its biological consequences, such as the role of Aβ chiral chemistry in regulating amyloid oligomerization, fibrillation and plaque deposition which are closely linked to the pathological development of AD. The impact of chirality on receptor recognition and binding process of these biologically active peptides, including Aβ, should be investigated Understanding these molecular changes and underlying mechanisms of chiral chemistry is very important but challenging for single/partial amino acid chiral inversion due to the analytical difficulty in distinguishing subtle structural differences induced by single/partial D-amino acid substitution.
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