阿尔茨海默病（AD）是一种破坏性疾病，目前治疗手段有限。本研究的目的是探索AD的病理生理学机制，以及探索可可的潜在神经保护效应，不论是单独应用可可还是与其他营养成分组合在一起，在铝诱导的AD动物模型中。实验中将大鼠分为九组：对照组、单独氯化铝（AlCl3）组、AlCl3与单独可可组、AlCl3与韦福司汀（VIN）组、AlCl3与表儿茶素-3-单加醇酸酯（EGCG）组、AlCl3与辅酶Q10（CoQ10）组、AlCl3与小麦草组（WG）、AlCl3与维生素B复合物组、以及AlCl3与维生素C、维生素E和硒的混合物组（Vit C, Vit E, Se）。对动物进行为期五周的处理，评估行为学、组织病理学和生化变化，重点关注氧化应激、炎症、Wnt/GSK-3β/β-连营本信号、内质网应激、自噬和凋亡等方面的变化。AlCl3处理引起氧化应激，在脑内显示出丙二醛（MDA）水平升高和细胞抗氧化剂（Nrf2、HO-1、SOD和TAC）表达下调。AlCl3还上调炎症生物标志物（TNF-α和IL-1β）和GSK-3β，导致tau蛋白磷酸化增加，脑源性神经营养因子（BDNF）表达降低，Wnt/β-连营本途径下调。此外，AlCl3加剧了C/EBP、p-PERK、GRP-78和CHOP的表达，表明持续的内质网应激，同时降低了Beclin-1和抗凋亡蛋白B细胞淋巴瘤2（Bcl-2）的表达。这些变化促成了AlCl3诱导AD模型中所观察到的行为和组织学改变。单独或与其他营养成分组合的可可治疗特别是VIN或EGCG的治疗，可显著改善所有评估参数。可可与营养成分的组合通过调节相互关联的病理生理途径，包括炎症、抗氧化应答、GSK-3β-Wnt/β-连营本信号、内质网应激和凋亡，减轻了AD所引起的恶化。这些发现为AD的复杂发病机制提供了洞察，并突显了营养成分通过多个信号途径发挥神经保护作用的重要性。

Alzheimer's disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.