Neurology Clinic, Torun, Poland.
Department of Crystallochemistry and Biocrystallography, Faculty of Chemistry, Nicolaus Copernicus University in Torun, Gagarina 7, 87-100, Torun, Poland.
Purinergic Signal. 2018 Dec;14(4):331-344. doi: 10.1007/s11302-018-9629-0. Epub 2018 Oct 25.
Etiology of the Alzheimer's disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces. Accumulation of amyloid-β (Aβ) in brain induces the ATP release into the extra-cellular space, which in turn stimulates the P2X7 receptors. Activation of P2X7 results in the increased synthesis and release of many pro-inflammatory mediators such as cytokines and chemokines. Furthermore, activation of P2X7 leads to the decreased activity of α-secretase, while activation of P2Y2 receptor has an opposite effect. Simultaneous inhibition of P2X7 and stimulation of P2Y2 would therefore be the efficient way of the α-secretase activation. Activation of P2Y2 receptors present in neurons, glia cells, and endothelial cells may have a positive neuroprotective effect in AD. The OS may also be counteracted via the purinergic signaling. ADP and its non-hydrolysable analogs activate P2Y13 receptors, leading to the increased activity of heme oxygenase, which has a cytoprotective activity. Adenosine, via A1 and A2A receptors, affects the dopaminergic and glutaminergic signaling, the brain-derived neurotrophic factor (BNDF), and also changes the synaptic plasticity (e.g., causing a prolonged excitation or inhibition) in brain regions responsible for learning and memory. Such activity may be advantageous in the Alzheimer's disease.
阿尔茨海默病（AD）的病因尚未完全阐明。不同的病理过程被认为与 AD 的发生有关，如淀粉样蛋白沉积、tau 蛋白磷酸化、氧化应激（OS）、金属离子失调或慢性神经炎症。嘌呤能信号参与了所有这些过程，提示核苷酸受体（P2X 和 P2Y）和腺苷受体（A1、A2A、A2B、A3）在中枢神经系统细胞上的重要性。细胞外嘌呤、嘧啶核苷及其代谢酶存在于细胞间隙中。脑内淀粉样蛋白-β（Aβ）的积累诱导 ATP 释放到细胞外间隙，进而刺激 P2X7 受体。P2X7 受体的激活导致许多促炎介质（如细胞因子和趋化因子）的合成和释放增加。此外，P2X7 受体的激活导致α-分泌酶活性降低，而 P2Y2 受体的激活则产生相反的效果。因此，同时抑制 P2X7 并刺激 P2Y2 将是激活α-分泌酶的有效方法。神经元、神经胶质细胞和内皮细胞上的 P2Y2 受体的激活可能对 AD 具有积极的神经保护作用。氧化应激也可以通过嘌呤能信号来对抗。ADP 及其非水解类似物激活 P2Y13 受体，导致血红素加氧酶活性增加，具有细胞保护作用。腺苷通过 A1 和 A2A 受体影响多巴胺能和谷氨酰胺能信号、脑源性神经营养因子（BDNF），并改变与学习和记忆相关的脑区的突触可塑性（例如，导致长时间的兴奋或抑制）。这种活性在阿尔茨海默病中可能是有益的。
