Bonzanni Mattia, Braga Alice, Saito Takashi, Saido Takaomi C, Tesco Giuseppina, Haydon Philip G
Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
iScience. 2024 Dec 18;28(1):111616. doi: 10.1016/j.isci.2024.111616. eCollection 2025 Jan 17.
The disease's trajectory of Alzheimer disease (AD) is associated with and negatively correlated to hippocampal hyperexcitability. Here, we show that during the asymptomatic stage in a knockin (KI) mouse model of Alzheimer disease (APP; APPKI), hippocampal hyperactivity occurs at the synaptic compartment, propagates to the soma, and is manifesting at low frequencies of stimulation. We show that this aberrant excitability is associated with a deficient adenosine tone, an inhibitory neuromodulator, driven by reduced levels of CD39/73 enzymes, responsible for the extracellular ATP-to-adenosine conversion. Both pharmacologic (adenosine kinase inhibitor) and non-pharmacologic (ketogenic diet) restorations of the adenosine tone successfully normalize hippocampal neuronal activity. Our results demonstrated that neuronal hyperexcitability during the asymptomatic stage of a KI model of Alzheimer disease originated at the synaptic compartment and is associated with adenosine deficient tone. These results extend our comprehension of the hippocampal vulnerability associated with the asymptomatic stage of Alzheimer disease.
阿尔茨海默病（AD）的病程与海马体过度兴奋相关且呈负相关。在此，我们表明，在阿尔茨海默病（APP；APPKI）基因敲入（KI）小鼠模型的无症状阶段，海马体的过度活跃发生在突触区室，传播到胞体，并在低频刺激时表现出来。我们表明，这种异常的兴奋性与腺苷张力不足有关，腺苷是一种抑制性神经调节剂，由负责细胞外ATP向腺苷转化的CD39/73酶水平降低所致。药理学（腺苷激酶抑制剂）和非药理学（生酮饮食）恢复腺苷张力均成功使海马体神经元活动恢复正常。我们的结果表明，KI阿尔茨海默病模型无症状阶段的神经元过度兴奋起源于突触区室，且与腺苷张力不足有关。这些结果扩展了我们对与阿尔茨海默病无症状阶段相关的海马体易损性的理解。
