Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
FASEB J. 2011 Sep;25(9):3208-18. doi: 10.1096/fj.10-180133. Epub 2011 May 18.
Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent α-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid β-peptide (Aβ) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Aβ-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD.
垂体腺苷酸环化酶激活肽（PACAP）具有神经保护和神经营养特性，是一种有效的α-分泌酶激活剂。由于 PACAP 肽及其特异性受体 PAC1 定位于受阿尔茨海默病（AD）影响的中枢神经系统区域，本研究旨在研究天然肽 PACAP 作为 AD 治疗有价值方法的作用。我们研究了 PACAP 在 AD 转基因小鼠模型大脑中的作用。长期鼻内每日 PACAP 应用刺激淀粉样前体蛋白（APP）的非淀粉样生成加工，并增加脑源性神经营养因子和抗凋亡 Bcl-2 蛋白的表达。此外，它还导致淀粉样 β 肽（Aβ）转运蛋白晚期糖基化终产物（RAGE）mRNA 水平的强烈降低。通过激活生长抑素-神经肽酶级联反应，PACAP 还增强了小鼠大脑中 Aβ 降解酶神经肽酶的表达。此外，通过 PACAP 对 PAC1 受体的每日激活导致 PAC1 受体及其配体 PACAP 的 mRNA 水平均增加。我们的行为研究表明，长期 PACAP 治疗 APP[V717I]-转基因小鼠改善了动物的认知功能。因此，PACAP 的鼻腔应用是有效的，我们的结果表明 PACAP 可能在治疗 AD 方面具有治疗价值。
