NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors

Melanocortins exert neuroprotection in a variety of experimental neurodegenerative disorders, including Alzheimer's disease (AD). Further, in previous research we showed that these endogenous peptides stimulate neurogenesis in an acute neurodegenerative disorder such as ischemic stroke. In the...

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Published in:	Molecular and cellular neuroscience 2015-07, Vol.67, p.13-21
Main Authors:	Giuliani, Daniela, Neri, Laura, Canalini, Fabrizio, Calevro, Anita, Ottani, Alessandra, Vandini, Eleonora, Sena, Paola, Zaffe, Davide, Guarini, Salvatore
Format:	Article
Language:	eng
Subjects:	alpha-MSH - adverse effects alpha-MSH - analogs & derivatives alpha-MSH - pharmacology alpha-MSH - therapeutic use Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer's disease Animals Cognition Functional integration Hippocampus - drug effects Learning and memory Melanocortin MC4 receptors Mice Neurogenesis Receptor, Melanocortin, Type 4 - agonists Receptor, Melanocortin, Type 4 - metabolism Tg2576 mice
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Summary:	Melanocortins exert neuroprotection in a variety of experimental neurodegenerative disorders, including Alzheimer's disease (AD). Further, in previous research we showed that these endogenous peptides stimulate neurogenesis in an acute neurodegenerative disorder such as ischemic stroke. In the present research, we investigated the potential neurogenic effect of melanocortins in AD using APPSwe transgenic mice (Tg2576). To this purpose, 24week-old animals were prepared for 5-bromo-2′-deoxyuridine (BrdU) labeling of proliferating cells on days 1–11 of the study. Treatment of Tg2576 mice with nanomolar doses of the melanocortin analog [Nle4,D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH), administered once daily from day 1 to 50, improved brain histology and cognitive functions relative to saline-treated Tg2576 animals. No signs of toxicity were observed. Immunohistochemical examination of the hippocampus at the end of the study (day 50) showed that NDP-α-MSH-treated Tg2576 mice had a greater number of BrdU immunoreactive cells colocalized with NeuN (an indicator of mature neurons) and Zif268 (an indicator of functionally integrated neurons) in the dentate gyrus, relative to saline-treated Tg2576 animals; no newly formed astrocytes were found. Animal pretreatment with the selective melanocortin MC4 receptor antagonist HS024 before each NDP-α-MSH administration prevented all the beneficial effects of the peptide. The present data indicate that MC4 receptor stimulation by a melanocortin prevents cognitive decline in experimental AD, this effect being associated not only with neuroprotection but also with an intense neurogenesis. MC4 receptor agonists could be innovative and safe candidates to counteract AD progression in humans. •Melanocortins induce neurogenesis in Alzheimer transgenic mice.•Newborn neurons functionally integrate.•Melanocortins counteract cognitive decline.•These effects are prevented by melanocortin MC4 receptor blockade.
ISSN:	1044-7431 1095-9327