Besides specific triggering causes,
Alzheimer's disease (AD) involves pathophysiological pathways that are common to acute and chronic
neurodegenerative disorders.
Melanocortins induce neuroprotection in experimental acute neurodegenerative conditions, and low
melanocortin levels have been found in occasional studies performed in AD-type
dementia patients. Here we investigated the possible neuroprotective role of
melanocortins in a chronic
neurodegenerative disorder, AD, by using 12-week-old (at the start of the study) triple-transgenic (3xTg-AD) mice harboring human transgenes APPSwe, PS1M146V, and tauP301L. Treatment of 3xTg-AD mice, once daily until the end of the study (30 weeks of age), with the
melanocortin analog [Nle(4),D-Phe(7)]-α-
melanocyte-stimulating hormone (NDP-α-
MSH) reduced cerebral cortex/hippocampus phosphorylation/level of all AD-related
biomarkers investigated (mediators of
amyloid/tau cascade, oxidative/nitrosative stress,
inflammation, apoptosis), decreased neuronal loss, induced over-expression of the synaptic activity-dependent gene Zif268, and improved cognitive functions, relative to saline-treated 3xTg-AD mice. Pharmacological blockade of
melanocortin MC4 receptors prevented all
neuroprotective effects of NDP-α-
MSH. Our study identifies, for the first time, a class of drugs,
MC4 receptor-stimulating
melanocortins, that are able to counteract the progression of experimental AD by targeting pathophysiological mechanisms up- and down-stream of β-
amyloid and tau. These data could have important clinical implications.