Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease
Summary: 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 (APPNL−G-F/NL−G-F; APPKI), hippocampal hyperactivity occurs a...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224028438 |
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| author | Mattia Bonzanni Alice Braga Takashi Saito Takaomi C. Saido Giuseppina Tesco Philip G. Haydon |
| author_facet | Mattia Bonzanni Alice Braga Takashi Saito Takaomi C. Saido Giuseppina Tesco Philip G. Haydon |
| author_sort | Mattia Bonzanni |
| collection | DOAJ |
| description | Summary: 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 (APPNL−G-F/NL−G-F; 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. |
| format | Article |
| id | doaj-art-ba57ebb7f90a40fab2a23c4f3416a9d2 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-ba57ebb7f90a40fab2a23c4f3416a9d22025-01-04T04:56:48ZengElsevieriScience2589-00422025-01-01281111616Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer diseaseMattia Bonzanni0Alice Braga1Takashi Saito2Takaomi C. Saido3Giuseppina Tesco4Philip G. Haydon5Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Corresponding authorDepartment of Neuroscience, Tufts University, Boston, MA 02111, USADepartment of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, JapanLaboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, JapanDepartment of Neuroscience, Tufts University, Boston, MA 02111, USADepartment of Neuroscience, Tufts University, Boston, MA 02111, USA; Corresponding authorSummary: 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 (APPNL−G-F/NL−G-F; 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.http://www.sciencedirect.com/science/article/pii/S2589004224028438Biological sciencesNeuroscienceMolecular neuroscience |
| spellingShingle | Mattia Bonzanni Alice Braga Takashi Saito Takaomi C. Saido Giuseppina Tesco Philip G. Haydon Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease iScience Biological sciences Neuroscience Molecular neuroscience |
| title | Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease |
| title_full | Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease |
| title_fullStr | Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease |
| title_full_unstemmed | Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease |
| title_short | Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease |
| title_sort | adenosine deficiency facilitates ca1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of alzheimer disease |
| topic | Biological sciences Neuroscience Molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224028438 |
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