Department of Basic Medical Sciences, Wrocław Medical University, Wrocław, Poland.
Laboratory of Virology, Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Curr Neuropharmacol. 2022;20(6):1144-1157. doi: 10.2174/1570159X19666211202124239.
Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.
最近的研究结果加深了我们对 AD 多因素性质的理解。虽然在 AD 的早期无症状阶段，淀粉样蛋白-β的合成和 tau 过度磷酸化起着关键作用，但在疾病的后期阶段，神经元、神经胶质细胞和脑血管内皮细胞中众多内稳态机制的功能障碍决定了临床症状进展的速度。高级神经退行性变的主要驱动因素包括神经元和神经胶质细胞中炎症反应的增加、氧化应激、神经元的神经营养生长和再生能力不足、脑胰岛素抵抗导致神经元代谢紊乱，或 Wnt-β 连环蛋白通路活性降低，该通路应整合脑组织的内稳态机制。为了更有效地抑制神经退行性变的进展，应该使用由纠正几种上述功能障碍的药物组成的联合治疗。值得注意的是，许多来自不同药理学组的广泛使用的药物，“除了”主要的治疗适应症外，对神经退行性变也有有益的影响，并可能在 AD 的联合治疗中引入临床实践。人们希望复杂的治疗将有效地抑制 AD 的进展，并将其转变为一种进展缓慢的慢性疾病。此外，随着大脑和微生物组之间双向通信机制的更好理解，预计这些途径将被利用来提供增强健康和治疗 AD 的新方法。
