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 [Nle(4),D-Phe(7)]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.