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    • However in recent years advanced

    2023-02-01

    However, in recent years advanced experiments and findings are emerging to give us more detailed information on Aβ-membrane interactions. Several reviews have provided background on the fibrillation of Aβ and the Aβ-membrane interactions [[18], [19], [20], [21], [22]]. In this review, we mainly focused on the new knowledge about Aβ-membrane interactions, and discussed the mechanisms of Aβ-membrane interaction and the structures of membrane-mediated Aβ aggregates.
    Aβ-membrane interactions
    Roles of Aβ-membrane interactions in Aβ aggregation
    Conclusions
    Conflict of interest
    Transparency document
    Introduction Alzheimer's disease (AD) is the most common form of dementia and is strongly correlated with the aggregation and fibril formation of the amyloid-β peptide (Aβ) [1]. Currently, no curative treatments are available, and the etiology of AD is still not fully understood. Amyloid formation of Aβ follows a nucleation-dependent polymerization process, which implies that a small assembly of Sitafloxacin Hydrate – a nucleus – must form first. The nucleus guides the peptides in assembling into a highly ordered fibrillar structure in a template-dependent manner. We will here refer to incorporation of monomers into oligomeric nuclei, as well as into fibrillar ends, as templating. Breaking of already existing fibrils also creates new sites that are amenable for the incorporation of monomers in a template-dependent manner. Fibril breakage in stagnant conditions of Aβ is however low [2]. In solution the formation of nuclei can occur de novo in a process referred to as primary nucleation [3], [4]. However, it has recently been demonstrated that already formed Aβ fibrils can catalyze the formation of new nuclei in a process called surface-catalyzed secondary nucleation (SCSN) also described as fibril catalyzed secondary nucleation [2], [3], [5], [6]. Because new fibril formation creates new catalytic sites, a positive feedback mechanism is generated whereby the rate of fibril formation increases exponentially even in stagnant solutions. Thus SCSN rapidly becomes the dominating path of Aβ fibril formation [2]. In vivo Aβ is a heterogeneous mixture of varying peptide lengths that are generated through proteolytic excision of the amyloid precursor protein. The clinically most relevant variants are the Aβ1–40 and Aβ1–42 peptides [7]. Fibrils of Aβ1–40 and Aβ1–42 differ significantly in their architecture [8], [9], [10], [11]. In addition, cell culture and animal studies suggest that Aβ1–42 assemblies are more cytotoxic than those of Aβ1–40 [12], [13]. Using Surface Plasmon Resonance (SPR) technique, where monomeric Aβ is probed against immobilized Aβ-fibrils [14], [15], [16], [17], [18], [19], [20], the nucleation step is circumvented and the process of elongation can be studied without any significant influence of SCSN (see material and methods for further details regarding this rationale). Thus, templating and cross-templating between varying peptide forms can also be studied. Using this approach, we found that monomeric Aβ1–42 can be readily incorporated into the ends of Aβ1–40 fibrils, while Aβ1–40 monomers are very poorly incorporated into Aβ1–42 fibrils. Our SPR results interestingly also showed that monomers incorporated into fibrils via cross-templating acquire the properties of the parental fibrils. The suppressed ability of Aβ1–40 to be incorporated within the fibrillar form of Aβ1–42, as well as the ability of Aβ1–42 monomers to acquire the properties of Aβ1–40 fibrils, might thus represent two intrinsic protective mechanism for lowering the total load of assemblies of the possibly more pathogenic Aβ1–42 fibrillar form.
    Results
    Discussion The in vivo deposition of Aβ is the result of an imbalance between the production and clearance of Aβ assemblies, and even small perturbations in this balance can have detrimental effects [27], [28], [29], [30], [31]. Aβ1–40 and Aβ1–42 fibrils, which are the most common Aβ variants in vivo, differ in their architectures [8], [9], [10], [11], and Aβ1–42 assemblies are associated with greater cytotoxic potential [12], [13]. Today much effort is focused on developing interfering agents including the use of both antibodies [32], [33], [34] and small molecules [35], [36]. In this context the link between cytotoxicity and structural properties is interesting to pursue, and factors altering the relative burden of a specific architectural form of Aβ are likely to alter its pathological impact. Previous studies that have investigated cross-seeding in solution between Aβ1–40 and Aβ1–42 report that the presence of Aβ1–40 monomers retards the assembly of Aβ1–42 monomers into fibrils, while the presence of Aβ1–42 monomers might accelerate the assembly of Aβ1–40 monomers into fibrils [37], [38], [39].