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 α-melanocyte stimulating hormone (α-MSH) attenuates GABAergic loss and thus improves cognition. TgCRND8 mice with established β-amyloid peptide pathology and nontransgenic littermates were treated with either α-MSH or vehicle via daily intraperitoneal injections for 28 d. TgCRND8 mice exhibited spatial memory deficits and altered anxiety that were rescued after α-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. α-MSH preserves GAD67 expression and prevents loss of the somatostatin-expressing subtype of GABAergic GAD67+ inhibitory interneurons. Without decreasing β-amyloid peptide load in the brain, α-MSH improves spatial memory in TgCRND8 mice and prevents alterations in anxiety. α-MSH modulated the excitatory-inhibitory balance in the brain by restoring GABAergic inhibition and, as a result, improved cognition in TgCRND8 mice.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Keran
K
Ma
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada j.mclaurin@utoronto.ca.
JoAnne
J
McLaurin
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000521:alpha-MSH / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000521:alpha-MSH
Alzheimer's disease; GABAergic system; cognitive function; somatostatin; α-melanocyte stimulating hormone