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Title: | Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice | Authors: | Rat, Dorothea Schmitt, Ulrich Tippmann, Frank DEWACHTER, Ilse Theunis, Clara Wieczerzak, Ewa Postina, Rolf van Leuven, Fred Fahrenholz, Falk Kojro, Elzbieta |
Issue Date: | 2011 | Publisher: | FEDERATION AMER SOC EXP BIOL | Source: | The FASEB journal, 25 (9) , p. 3208 -3218 | Abstract: | 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. | Keywords: | PAC1 receptor;G-protein-coupled receptor;neuroprotection;nasal delivery | Document URI: | http://hdl.handle.net/1942/30300 | ISSN: | 0892-6638 | e-ISSN: | 1530-6860 | DOI: | 10.1096/fj.10-180133 | ISI #: | 000294435200033 | Rights: | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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