α-Melanocyte Stimulating Hormone Prevents GABAergic Neuronal Loss and Improves Cognitive Function in Alzheimer's Disease

In Alzheimer's disease (AD), appropriate excitatory-inhibitory balance required for memory formation is impaired. Our objective was to elucidate deficits in the inhibitory GABAergic system in the TgCRND8 mouse model of AD to establish a link between GABAergic dysfunction and cognitive function. We sought to determine whether the neuroprotective peptide alpha-melanocyte stimulating hormone (alpha-MSH) attenuates GABAergic loss and thus improves cognition. TgCRND8 mice with established beta-amyloid peptide pathology and nontransgenic littermates were treated with either alpha-MSH or vehicle via daily intraperitoneal injections for 28 d. TgCRND8 mice exhibited spatial memory deficits and altered anxiety that were rescued after alpha-MSH treatment. The expression of GABAergic marker glutamic acid decarboxylase 67 (GAD67) and the number of GABAergic GAD67+ interneurons expressing neuropeptide Y and somatostatin are reduced in the hippocampus in vehicle-treated TgCRND8 mice. In the septohippocampal pathway, GABAergic deficits are observed before cholinergic deficits, suggesting that GABAergic loss may underlie behavior deficits in vehicle-treated TgCRND8 mice. alpha-MSH preserves GAD67 expression and prevents loss of the somatostatin-expressing subtype of GABAergic GAD67+ inhibitory interneurons. Without decreasing beta-amyloid peptide load in the brain, alpha-MSH improves spatial memory in TgCRND8 mice and prevents alterations in anxiety. alpha-MSH modulated the excitatory-inhibitory balance in the brain by restoring GABAergic inhibition and, as a result, improved cognition in TgCRND8 mice.