Han Pengcheng, Nielsen Megan, Song Melissa, Yin Junxiang, Permenter Michele R, Vogt Julie A, Engle James R, Dugger Brittany N, Beach Thomas G, Barnes Carol A, Shi Jiong
Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical CenterPhoenix, AZ, United States.
Department of Pathology and Laboratory Medicine Resident Program, Medical University of South CarolinaCharleston, SC, United States.
Front Aging Neurosci. 2017 Jun 12;9:180. doi: 10.3389/fnagi.2017.00180. eCollection 2017.
Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.
垂体腺苷酸环化酶激活多肽（PACAP）与阿尔茨海默病（AD）相关，但其与年龄相关的影响尚不清楚。由于恒河猴在解剖学和生理学上与人类相近，我们选择了恒河猴作为研究对象。我们研究了四个变量：衰老、认知能力、淀粉样斑块和PACAP。延迟非匹配样本识别记忆分数随年龄下降，并与纹状体、顶叶和颞叶中的PACAP水平相关。由于淀粉样斑块是老年恒河猴唯一的AD病理学特征，我们进一步研究了人淀粉样前体蛋白（hAPP）转基因小鼠。衰老与莫里斯水迷宫（MWM）中的表现下降有关。在野生型（WT）C57BL/6小鼠中，24 - 26月龄时表现下降，而在hAPP转基因小鼠中，早在9 - 12月龄时表现就下降了。成年hAPP小鼠的神经炎性斑块聚集在海马体和相邻的皮质区域，但没有进一步扩散到额叶皮质。与年龄匹配的WT小鼠相比，hAPP小鼠大脑中的PACAP蛋白水平降低，但遗传易感性主导了认知能力下降。综上所述，这些数据表明在非人类灵长类动物中，PACAP水平、衰老、认知功能和淀粉样负荷之间存在关联，与人类AD大脑既有相似之处也有不同之处。我们的结果表明在选择动物模型以及将数据外推至人类AD研究时需谨慎。
