Human Histology & Embryology Unit, University of Verona Medical School, Verona, Venetia. Italy.
National Research Council of Canada, Ottawa, Ontario. Canada.
Curr Pharm Des. 2017;23(33):4990-5000. doi: 10.2174/1381612823666170710162509.
Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides. Aβ•CaSR signalling in NAHAs also drives the release of toxic hyper-phosphorylated Tau proteins in exosomes, and of nitric oxide, and VEGF-A. These several harmful agents comprise the neuron-killing machinery, driving the very slowly spreading AD neurocontagion. VEGF-A over-secretion from Aβ-exposed blood vessel-attached astrocytes induces a functional magnetic resonance imaging- detectable hippocampal neoangiogenesis which indicates approaching AD in amnestic minor cognitive impairment (aMCI) patients. Most important in AD's regard, selective allosteric CaSR antagonists (calcylitics) added to Aβ42/Aβ42-os-exposed NAHAs (or to human neuron cultures) rescue the extracellular shedding of neurotrophic/ neuroprotective sAPPα and suppress all the neurotoxic effects of Aβ•CaSR signalling even when multiple microglial cytokines are also present. Therefore, since the multipotent calcilytics would be reasonably safe and inexpensive drugs for humans, it is worthwhile testing them as AD therapeutics in clinical trials especially in persons in the earliest detectable stages of AD neuropathology progression such as aMCI.
了解阿尔茨海默病（AD）的病理生理学对于寻找这种疾病的治疗方法是必要的。为此，我们一直在使用新鲜培养的功能正常的成人大脑皮质星形胶质细胞（NAHAs）和产后神经元。研究结果表明，淀粉样β寡聚体（Aβ-os）与 NAHAs 和神经元表面的钙敏感受体（CaSRs）结合，触发能够驱动 AD 发病机制的信号。这种 Aβ•CaSR 信号将淀粉样前体蛋白（APP）从其α-分泌酶切割产生神经营养/神经保护可溶性（s）APPα转移到其β-分泌酶切割产生 AD 驱动的 Aβ42/Aβ42-os 肽。NAHAs 中的 Aβ•CaSR 信号还会驱动毒性磷酸化 Tau 蛋白在细胞外体中的释放，以及一氧化氮和 VEGF-A 的释放。这些几种有害因子构成了杀伤神经元的机制，驱动着非常缓慢传播的 AD 神经传染病。Aβ 暴露的血管附着星形胶质细胞中 VEGF-A 的过度分泌会诱导功能磁共振成像可检测到的海马新血管生成，这表明在遗忘型轻度认知障碍（aMCI）患者中 AD 即将发生。在 AD 方面最重要的是，在 Aβ42/Aβ42-os 暴露的 NAHAs（或人神经元培养物）中添加选择性变构 CaSR 拮抗剂（calcylitics）可挽救神经营养/神经保护 sAPPα 的细胞外脱落，并抑制 Aβ•CaSR 信号的所有神经毒性作用，即使存在多种小胶质细胞细胞因子也是如此。因此，由于多潜能的 calcylitics 对人类来说是合理安全且廉价的药物，因此值得在临床试验中测试它们作为 AD 治疗药物，尤其是在那些处于 AD 神经病理学进展最早可检测阶段的患者，如 aMCI。
