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    • br Acknowledgments br Introduction Alzheimer s disease AD

    2022-11-07


    Acknowledgments
    Introduction Alzheimer's disease (AD) is a severe neurodegenerative disorder primarily affecting the elderly population. Senile plaques in the brain, one of the pathological hallmarks of AD, are formed by the accumulation of aggregated β-amyloid (Aβ) with an extensive β-sheet structure [1]. The successful aggregation of Aβ monomers into oligomers and fibrils is strongly associated with the onset of neurotoxicity [2]. Aβ is derived from amyloid precursor protein (APP) through sequential proteolytic cleavages by β-secretase and further cleavage by γ-secretase [3], [4]. Aβ peptides are primarily classified into two major molecular species, Aβ(1–40) and Aβ(1–42), depending on the length of the C-terminal region cleaved by γ-secretase. Although Aβ(1–40) is the predominant product, Aβ(1–42) is more aggregative and neurotoxic [2] and is the form initially deposited in the Valrocemide australia [5], [6]. Studies indicate that the deposition of Aβ(1–43) is more common than Aβ(1–40) in sporadic AD (SAD) and familial AD (FAD) [7], [8], [9] and that Aβ(1–43) is potently amyloidogenic, neurotoxic, and abundant in vivo[10]. Moreover, [Pyr3]-Aβ(3–42), in which the third amino-terminal residue of the normal Aβ, glutamate, is converted to pyroglutamate by intramolecular dehydration, is deposited in senile plaques in a dominant and differential manner compared with normal Aβs [11]. Many genetic alterations were found in FAD and cerebral amyloid angiopathy (CAA), including Flemish (A21G) [12], [13], [14], which alters APP processing and increases secreted Aβ, English (H6R) [15], [16], Arctic (E22G) [17], [18], Dutch (E22Q) [19], [20], [21], and Iowa (D23 N) [22], [23], which accelerate Aβ aggregation and increase cytotoxicity, and Italian (E22K) [24], which is related to CAA. Memantine, an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, selectively blocks the excitotoxic effects of glutamate, including the pathological influx of Ca2+ and oxidative stress in postsynaptic neurons, while preserving physiological transmission for normal cellular function [25]. The neuroprotective effects of memantine on Aβ and/or excitotoxicity were demonstrated in animal studies [26], [27]. Furthermore, several studies and our study indicated that memantine decreased Aβ levels in the brains of animal models of AD, including in APP/PS1 Tg mice [28], [29], Tg2576 mice [30], [32], and triple-transgenic mice [which express three dementia-related transgenes (APPSWE, presenilin-1M146V, and tauP301L)] [31], and caused an age-dependent accumulation of Aβ in normal F344 rats [32]. The possible mechanisms underlying the actions of memantine in reducing the number of Aβ plaques in the brain include inhibition of Aβ production, inhibition of Aβ aggregation, and acceleration of Aβ degradation. We proposed that memantine might reduce Aβ production and plaque deposition via regulation of the intracellular trafficking of APP [32]. Here we evaluated whether memantine inhibited Aβ aggregation or dissociated Aβ fibrils using thioflavin T (ThT) as a fluorescent marker of amyloid fibrils and transmission electron microscopy (TEM).
    Materials and methods
    Results
    Discussion Here we showed that memantine inhibited the formation of Aβ fibrils and disaggregated preformed Aβ fibrils in vitro, suggesting that memantine has the potential to not only prevent Aβ aggregation but also promote the disassembly of deposited Aβ aggregates. Furthermore, memantine decreased the Aβ oligomer levels, indicating that memantine directly reduces the formation of Aβ fibrils and oligomers. To date, several studies and our study indicated that memantine decreased the levels of insoluble Aβs in transgenic mouse models of AD and aged F344 rats [28], [29], [30], [31], [32]. We proposed that the reduction of Aβ production by memantine via regulation of intracellular APP translocation might reduce Aβ levels in the brain of such animals [32]. Here we propose that the direct effect of memantine on Aβ aggregates is involved in the mechanisms by which memantine reduces brain Aβ levels.