Pimentel Luisa S, Allard Simon, Do Carmo Sonia, Weinreb Orly, Danik Marc, Hanzel Cecilia E, Youdim Moussa B, Cuello A Claudio
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Abital Pharma Pipeline Ltd., Tel Aviv, Israel.
J Alzheimers Dis. 2015;47(2):373-83. doi: 10.3233/JAD-143126.
Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.
目前针对阿尔茨海默病（AD）的治疗方法只能部分缓解症状，无法改变疾病的进展。有大量证据表明，该病在临床诊断前数年就已发病，而此时尚未发现有效的治疗方法。在本研究中，我们在一个强健的大鼠转基因模型中，研究了一种新型多靶点药物M30在类AD淀粉样病理相对早期阶段的疗效。McGill-R-Thy1-APP转基因大鼠会以渐进方式发展出完全类AD淀粉样病理，且遗传负担极小。从转基因动物出现可检测到的认知障碍阶段开始，每隔一天给McGill大鼠口服5毫克/千克的M30或赋形剂，持续4个月。治疗结束时，通过新物体定位和新物体识别测试评估认知功能。然后对大脑进行分析，以评估淀粉样β蛋白（Aβ）负荷和关键炎症标志物的水平。长期使用M30治疗与预防和逆转转基因相关的认知衰退有关。对认知的影响伴随着Aβ免疫反应性物质向淀粉样斑块聚集分子形式的转变、中枢神经系统炎症分子迹象的减少以及小胶质细胞形态向监测表型的变化。本研究首次证明了M30在AD淀粉样病理大鼠模型中的治疗潜力。它为进一步研究M30以及采用潜在的多靶点方法在疾病早期阶段延迟、预防或逆转AD病理进展提供了理论依据。
