Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
J Neurosci. 2014 May 14;34(20):6736-45. doi: 10.1523/JNEUROSCI.5075-13.2014.
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.
在阿尔茨海默病（AD）中，记忆形成所需的适当兴奋-抑制平衡受损。我们的目标是阐明 AD 的 TgCRND8 小鼠模型中抑制性 GABA 能系统的缺陷，以建立 GABA 能功能障碍与认知功能之间的联系。我们试图确定神经保护肽α-促黑素细胞激素（α-MSH）是否减轻 GABA 能丧失，从而改善认知。用每日腹腔内注射α-MSH 或载体处理具有稳定β-淀粉样肽病理学的 TgCRND8 小鼠及其非转基因同窝仔 28d。α-MSH 处理后，TgCRND8 小鼠表现出空间记忆缺陷和焦虑改变，这些改变得到了挽救。在载体处理的 TgCRND8 小鼠的海马中，GABA 能标志物谷氨酸脱羧酶 67（GAD67）的表达和表达神经肽 Y 和生长抑素的 GABA 能 GAD67+中间神经元的数量减少。在隔海马通路上，在胆碱能缺陷之前观察到 GABA 能缺陷，这表明 GABA 能丧失可能是载体处理的 TgCRND8 小鼠行为缺陷的基础。α-MSH 可维持 GAD67 的表达并防止表达生长抑素的 GABA 能 GAD67+抑制性中间神经元的丧失。在不减少脑内β-淀粉样肽负荷的情况下，α-MSH 可改善 TgCRND8 小鼠的空间记忆并防止焦虑改变。α-MSH 通过恢复 GABA 能抑制作用来调节大脑的兴奋-抑制平衡，从而改善 TgCRND8 小鼠的认知能力。
