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  • Aggregated A species have been studied by an array of

    2024-02-07

    Aggregated Aβ species have been studied by an array of biophysical techniques, including atomic force microscopy (AFM) [55], transmission electron microscopy (TEM) [56], [57], X-ray diffraction [58], Fourier transform infrared (FTIR) [59], [60], circular dichroism (CD) [61], and nuclear magnetic resonance (NMR) spectroscopies [62], [63]. However, most of these methods allow determination of only the relative population of secondary structures or provide information on the overall fold of the molecular species. Obtaining atomic resolution structures of oligomers or fibrils has proven to be extremely challenging. Conventional high resolution structural methods such as X-ray crystallography or solution NMR predominantly provide only a limited understanding of the studied structures. For instance, fibrils are highly ordered on the molecular level and fiber diffraction allows identification of a common motif in fibrils termed as the “cross-β structure”, which contains a set of β-sheets parallel to the fibril axis with the extended strands close to perpendicular to the axis. However, on the microscopic scale fibrils are disordered and do not diffract to high resolution [64]. Characterization of oligomers by solution NMR is hindered by the vast trans-4-Hydroxycrotonic acid synthesis of oligomer structures and by their transient nature [65], [66], [67]. Furthermore, these intermediate species often have high molecular weights (>40 kDa) leading to extremely broad peaks that are generally not detectable as a result of very fast spin relaxation [57], [68]. Recently, solid state NMR (ssNMR) has emerged as a technique that allows elucidation of high resolution structures of both oligomers and fibrils [62], [69], [70]. Moreover, using state-of-the-art solution NMR techniques, it has been possible to probe the conformation of otherwise NMR-invisible states [68], [71]. Development of new therapeutic strategies against AD requires advancing our understanding of the underlying mechanisms of Aβ aggregation and the associated toxicity. For instance, monomeric Aβ could be exploited as a therapeutic target and many substances that interact with monomeric Aβ have been identified to inhibit or modulate the aggregation of Aβ in the presence or absence of metal ions [32], [37], [39], [40], [41], [42], [72]. Additionally, it has been demonstrated that Aβ1-42 fibrils catalyze the formation of toxic oligomeric species [73], [74]. Thus, all Aβ forms are significant to the progression of AD and much effort has been invested in biophysical and structural characterization of these species. Currently, the only technique capable of providing residue specific structural information of all Aβ forms is NMR. This review was inspired by recent progress in Aβ structural research. Most notably, in recent years three separate research groups published the fibril structure of Aβ1-42[75], [76], [77]. Furthermore, comprehensive experimental studies have been reported on oligomer-membrane interactions and monomer structure providing new insights to the understanding of toxicity and aggregation mechanism on a molecular level [54], [78], [79]. Thus, this review describes recent results of structural studies of monomeric and aggregated Aβ peptide forms, with a focus on solution and solid state NMR studies. We start by providing a review on the structure of monomeric Aβ and subsequently discuss the possible implications on the aggregation mechanism. We then summarize what is known about intermediate aggregate structures and evaluate their relevance to the mechanism of toxicity. Finally, we discuss recent results of fibril structural studies and supplement our conclusions from the previous sections.
    Structure of monomeric Aβ peptide and implications for the mechanism of aggregation Structural investigations of monomeric Aβ peptide are often regarded as less significant than studies of oligomers or fibrils because this form lacks any apparent toxicity. Nevertheless, monomeric Aβ has been recognized as a potential drug target since inhibition of the monomer aggregation could prevent the formation of toxic species [32] and it is known that species differences in the amino acid sequence increase or reduce aggregation behavior in vivo[80]. Thus, structural research of the peptide can promote the understanding of the aggregation mechanism and facilitate the development of treatment strategies against AD. Moreover, Aβ is necessary for the normal function of the nervous system and structural information of the peptide can also advance research on its physiological role.