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  • It has been reported that trehalose shows beneficial effects

    2024-07-11

    It has been reported that trehalose shows beneficial effects in a mouse model of several neurodegenerative diseases [21], [22], [23]. There are also reports showing that trehalose can improve the impaired cognitive and learning ability and reduced Aβ deposit in hippocampus of APP/PS1 transgenic mice [24]. However, the role of trehalose in reducing Aβ peptide aggregation is still not clear. It is known that in solution at room temperature and physiological pH, Aβ peptide exists in a dominating random coil secondary structure [25], but can undergo structural conversions between random coil and more structured β-strand conformations, which is selected to from oligomers through interactions between these β-strand conformations [7], [26], [27], [28]. In the present study, we determined whether trehalose can induce a conformational transition in Aβ peptide. Our results demonstrate that in the presence of trehalose, Aβ peptide undergoes a disorder/order conformational transition in a cooperative manner.
    Materials and methods
    Results
    Discussion Alzheimer disease affects millions of people world-wide, yet there are currently no effective treatments targeting the underlying molecular cause of this debilitating neurodegenerative disease [40], [41], [42], [43], [44]. One of the major pathologies of Alzheimer disease involves accumulation of extracellular proteinaceous insoluble plaques composed of amyloid, a fibrillar form of protein. Several pathogenic species that precede plaque formation have been isolated from Alzheimer disease brains; however, exact pathway of Aβ peptide aggregation is not fully understood. A general view of the aggregation of soluble monomers into insoluble fibrils involves the growth of the β-sheet-rich oligomers into higher order cgrp antagonist [45], [46]. The link between Aβ peptide aggregation, cellular dysfunction, and Alzheimer disease suggests that inhibition of Aβ peptide oligomerization may ultimately lead to therapeutics that prevent and/or treat Alzheimer's disease [47], [48], [49], [50]. Therefore, identification of small molecules that could decrease the Aβ peptide aggregates may prove critical for targeted drug discovery against Alzheimer disease [51]. However, to date, no compounds have entered into clinical use. Here, we focused on a therapeutically important saccharide molecule, trehalose that could potentially halt/reverse misfolding, trap structurally unstable/partially folded intermediates leading to attenuation of aggregation. Saccharide molecules play a number of fundamentally important roles in the brain and there is growing evidence that naturally derived saccharides such as trehalose have beneficial effects on brain function, demonstrated as both cellular and functional effects in terms of neuroprotection and improvements in cognition. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of neurodegenerative diseases. Several studies have shown that trehalose has the ability to stabilize protein folding and induce autophagy, thereby decreasing the toxicity of abnormal protein aggregates in the CNS [22]. Our in vitro experiments have shown that trehalose affects the conformation of Aβ-40 peptide to form an α-helical structure, which may inhibit the formation of β-sheets and thereby aggregation. Trehalose has previously been shown to reverse the cytotoxicity caused by Aβ-40 [22]. In an Alzheimer's disease animal model, trehalose has also been shown to prevent the appearance of apoptosis in hippocampus and cerebral cortex and significantly reduced levels of Aβ-40 peptide aggregates [24]. Further studies have demonstrated that trehalose improves cognitive and learning ability of experimental animals and reduced Aβ deposits in hippocampus of APP/PS1 transgenic mice [24].
    Introduction Hyperphosphorylated tau and amyloid-β (Aβ) are the constituents of neurofibrillary tangles (NFT) and amyloid plaques, respectively, 2 major pathologies in Alzheimer disease (AD). The 2 proteins accumulate and spread in specific hierarchical patterns. Cortical Aβ spreads from the frontotemporal cortices to involve widespread neocortical areas (Thal's Aβ phase 1) and eventually reaches the medial temporal structures (phase 2) (Braak and Braak, 1991, Thal et al., 2002). In contrast, cortical tau spreads in a stepwise hierarchical pattern from the transentorhinal and entorhinal cortices (Braak's NFT stage I and II) toward the neighboring medial temporal structures (stage III and IV) and distant association cortices (stage V) and eventually reaches the primary cortices (stage VI) (Braak and Braak, 1991).