Han Pengcheng, Tang Zhiwei, Yin Junxiang, Maalouf Marwan, Beach Thomas G, Reiman Eric M, Shi Jiong
Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA.
Department of Neurology, Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ, USA; Department of Neurosurgery, The First Hospital of Kunming Medical University, Kunmming, China.
Neurobiol Aging. 2014 Sep;35(9):2064-71. doi: 10.1016/j.neurobiolaging.2014.03.022. Epub 2014 Mar 22.
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophin. However, its role in human Alzheimer's disease (AD) is largely unknown. We examined PACAP expression in postmortem human AD and triple transgenic mouse (3xTG, Psen1/APPSwe/TauP301L) brains. We established an in vitro model of primary neuronal cell culture to study the protective effects of PACAP against β-amyloid (Aβ) toxicity. We further studied the PACAP-Sirtuin 3 (Sirt3) pathway on mitochondrial function. PACAP expression was reduced in AD and 3xTG mouse brains. This reduction was inversely correlated with Aβ and tau protein levels. Treatment with PACAP effectively protected neurons against Aβ toxicity. PACAP stimulated mitochondrial Sirt3 production. Similar to PACAP, Sirt3 was reduced in AD and 3xTG brains. Knocking down Sirt3 compromised the neuroprotective effects of PACAP, and this was reversed by over-expressing Sirt3. PACAP is reduced in AD and may represent a novel therapeutic strategy.
垂体腺苷酸环化酶激活多肽（PACAP）是一种神经营养因子。然而，其在人类阿尔茨海默病（AD）中的作用在很大程度上尚不清楚。我们检测了人AD死后大脑以及三转基因小鼠（3xTG，Psen1/APPSwe/TauP301L）大脑中PACAP的表达。我们建立了原代神经元细胞培养的体外模型，以研究PACAP对β-淀粉样蛋白（Aβ）毒性的保护作用。我们进一步研究了PACAP-沉默调节蛋白3（Sirt3）通路对线粒体功能的影响。AD和3xTG小鼠大脑中PACAP表达降低。这种降低与Aβ和tau蛋白水平呈负相关。用PACAP处理可有效保护神经元免受Aβ毒性。PACAP刺激线粒体Sirt3的产生。与PACAP相似，AD和3xTG大脑中Sirt3也减少。敲低Sirt3会损害PACAP的神经保护作用，而过表达Sirt3可逆转这种作用。AD中PACAP减少，这可能代表一种新的治疗策略。
