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J Neurosci. 2014 May 14;34(20):6736-45. doi: 10.1523/JNEUROSCI.5075-13.2014.

α-Melanocyte stimulating hormone prevents GABAergic neuronal loss and improves cognitive function in Alzheimer's disease.

Author information

1
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada j.mclaurin@utoronto.ca.

Abstract

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.

KEYWORDS:

Alzheimer's disease; GABAergic system; cognitive function; somatostatin; α-melanocyte stimulating hormone

PMID:
24828629
DOI:
10.1523/JNEUROSCI.5075-13.2014
[Indexed for MEDLINE]
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