Department of Health Science, Institute of Research for Food Safety & Health (IRC-FSH), University Magna Græcia of Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, Italy.
Int J Mol Sci. 2023 Aug 30;24(17):13461. doi: 10.3390/ijms241713461.
Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of extracellular aggregates of beta-amyloid proteins and neurofibrillary intracellular tangles consisting of τ-hyperphosphorylated proteins. Under normal conditions, beta-amyloid peptides exert important trophic and antioxidant roles, while their massive presence leads to a cascade of events culminating in the onset of AD. The fibrils of beta-amyloid proteins are formed by the process of fibrillogenesis that, starting from individual monomers of beta-amyloid, can generate polymers of this protein, constituting the hypothesis of the "amyloid cascade". To date, due to the lack of pharmacological treatment for AD without toxic side effects, chemical research is directed towards the realization of hybrid compounds that can act as an adjuvant in the treatment of this neurodegenerative pathology. The hybrid compounds used in this work include moieties of a hydroxytyrosol, a nitrohydroxytyrosol, a tyrosol, and a homovanillyl alcohol bound to the N-benzylpiperidine moiety of donepezil, the main drug used in AD. Previous experiments have shown different properties of these hybrids, including low toxicity and antioxidant and chelating activities. The purpose of this work was to test the effects of hybrid compounds mixed with A to induce fibrillogenesis and mimic AD pathogenesis. This condition has been studied both in test tubes and by an in vitro model of neuronal differentiated human SH-SY5Y neuroblastoma cells. The results obtained from test tube experiments showed that some hybrids inhibit the activity of the enzymes AChE, BuChE, and BACE-1. Cell experiments suggested that hybrids could inhibit fibrillogenesis, negatively modulating caspase-3. They were also shown to exert antioxidant effects, and the acetylated hybrids were found to be more functional and efficient than nonacetylated forms.
阿尔茨海默病（AD）是进行性痴呆中最常见的神经退行性病变，其特征是脑内β淀粉样蛋白的细胞外聚集物和由τ过度磷酸化蛋白组成的神经原纤维细胞内缠结的积累。在正常情况下，β淀粉样肽发挥着重要的营养和抗氧化作用，而大量存在则会导致一系列事件，最终导致 AD 的发生。β淀粉样蛋白纤维由纤维原纤维形成过程形成，该过程从β淀粉样蛋白的单个单体开始，可以生成该蛋白的聚合物，构成了“淀粉样蛋白级联”假说。迄今为止，由于缺乏无毒性副作用的 AD 治疗药物，化学研究的方向是实现可以作为这种神经退行性病变治疗辅助剂的混合化合物。在这项工作中使用的混合化合物包括羟基酪醇、硝基羟基酪醇、酪醇和高香草醇的部分与多奈哌齐的 N-苄基哌啶部分结合，多奈哌齐是 AD 中主要使用的药物。以前的实验表明这些混合物具有不同的性质，包括低毒性、抗氧化和螯合活性。这项工作的目的是测试混合化合物与 A 混合诱导纤维原纤维形成并模拟 AD 发病机制的效果。这种情况在试管中和通过体外分化的人 SH-SY5Y 神经母细胞瘤细胞的模型中进行了研究。试管实验结果表明，一些混合物抑制 AChE、BuChE 和 BACE-1 酶的活性。细胞实验表明，混合物可以抑制纤维原纤维形成，负调控半胱天冬酶-3。它们还显示出抗氧化作用，并且发现乙酰化的混合物比非乙酰化形式更有效。
