Campbell Shannon N, Zhang Cheng, Roe Allyson D, Lee Nickey, Lao Kathleen U, Monte Louise, Donohue Michael C, Rissman Robert A
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA Department of Family Preventive Medicine, University of California, San Diego, La Jolla, CA, USA.
J Alzheimers Dis. 2015;45(4):1175-84. doi: 10.3233/JAD-142844.
Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer's disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-β (Aβ) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in an AD transgenic model and whether this type of treatment could impact Aβ pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1(+/-)) and homozygous (PSAPP-R1(-/-)) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Aβ levels and pathology. We found that both PSAPP-R1(+/-) and PSAPP-R1(-/-) had significantly reduced Aβ burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Aβ peptides and AβPP-CTFs, providing support for a direct relationship between CRFR1 and Aβ production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Aβ neuropathology.
应激暴露和促肾上腺皮质激素释放因子（CRF）系统被认为在阿尔茨海默病（AD）及其相关啮齿动物模型中存在机制性关联。特别是主要应激受体1型CRF受体（CRFR1），可调节许多与AD相关脑区的细胞活性，并已被证明会影响tau蛋白磷酸化和淀粉样β蛋白（Aβ）通路。我们实验室的总体目标是开发并表征能够影响CRF信号系统的药物，作为AD的疾病修饰治疗方法。在本研究中，我们培育了一种新型转基因小鼠，以确定在AD转基因模型中部分或完全敲除CRFR1是否可行，以及这种治疗方式是否会影响Aβ病理。将双转基因AD小鼠（PSAPP）与CRFR1基因敲除小鼠杂交；所得的CRFR1杂合子（PSAPP-R1(+/-)）和纯合子（PSAPP-R1(-/-)）雌性后代在12月龄时用于检查CRFR1缺失对AD中Aβ水平和病理严重程度的影响。我们发现，PSAPP-R1(+/-)和PSAPP-R1(-/-)小鼠海马体、岛叶、嗅周皮质和压后皮质中的Aβ负担均显著降低。因此，我们观察到Aβ肽和AβPP-CTF显著减少，这为CRFR1与Aβ产生途径之间的直接关系提供了支持。总之，我们的结果表明，在AD模型中干扰CRFR1是可耐受的，并且在影响Aβ神经病理学方面是有效的。
