Role of the late‐onset Alzheimer’s disease risk genes bin1 and ptk2b in the hyperexcitability of hiPSC‐derived neurons

Background The BIN1 (Bridging Integrator‐1) gene is the second most important Alzheimer’s disease risk gene and has been associated with synaptic transmission defects in animal models. PTK2B (Protein Tyrosine Kinase 2β) is a Ca2+‐activated non‐receptor tyrosine kinase, also identified by genome‐wide...

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Published inAlzheimer's & dementia Vol. 17; pp. e053632 - n/a
Main Authors De Farias, Ana‐Raquel Melo, Saha, Orthis, Lambert, Jean‐Charles, Costa, Marcos Romualdo
Format Journal Article
LanguageEnglish
Published United States 01.12.2021
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Abstract Background The BIN1 (Bridging Integrator‐1) gene is the second most important Alzheimer’s disease risk gene and has been associated with synaptic transmission defects in animal models. PTK2B (Protein Tyrosine Kinase 2β) is a Ca2+‐activated non‐receptor tyrosine kinase, also identified by genome‐wide association study (GWAS) as an important AD risk factor, and playing a role in the mouse hippocampal synaptic plasticity. Method In this work, we aimed at studying the possible effects of BIN1 or PTK2B underexpression in the electrical activity taking advantage of human induced pluripotent stem cell (hiPSC)‐derived neurons. To this aim, we are using hiPSCs expressing allelic variants of BIN (BIN1+/+ and BIN1‐/‐) or PTK2B (PTK2B+/+, PTK2B+/‐ and PTK2B ‐/‐). Human induced neural progenitor cells (hiNPCs) are generated from these hiPSCs, which are further differentiated into mature neurons and glia. We evaluated the gene expression, cell type composition of cultures, and neuronal electrical activity using western blot, immunocytochemistry, pharmacological assays, and calcium imaging as a readout of the electrical function. Result Our preliminary data suggest that BIN1 KO decreases proliferation of NPCs. In addition, analyses of calcium imaging recordings show decreased number of active cells although, the active ones show a higher calcium spikes frequency and less synchronization. Furthermore, neuronal activity or PTK2B underexpression impairs the differentiation potential of hiNPCs into neurons. As well, and increased calcium spikes frequency in hiNs. Conclusion Taken together, our preliminary panel of data suggests that both BIN1 and PTK2B regulate important biological processes involved in neuronal differentiation and electrical maturation. Thus, altered expression of these genes in the AD brain could play a role in neuronal hyperexcitability observed in patients.
AbstractList The BIN1 (Bridging Integrator-1) gene is the second most important Alzheimer's disease risk gene and has been associated with synaptic transmission defects in animal models. PTK2B (Protein Tyrosine Kinase 2β) is a Ca -activated non-receptor tyrosine kinase, also identified by genome-wide association study (GWAS) as an important AD risk factor, and playing a role in the mouse hippocampal synaptic plasticity. In this work, we aimed at studying the possible effects of BIN1 or PTK2B underexpression in the electrical activity taking advantage of human induced pluripotent stem cell (hiPSC)-derived neurons. To this aim, we are using hiPSCs expressing allelic variants of BIN (BIN1+/+ and BIN1-/-) or PTK2B (PTK2B+/+, PTK2B+/- and PTK2B -/-). Human induced neural progenitor cells (hiNPCs) are generated from these hiPSCs, which are further differentiated into mature neurons and glia. We evaluated the gene expression, cell type composition of cultures, and neuronal electrical activity using western blot, immunocytochemistry, pharmacological assays, and calcium imaging as a readout of the electrical function. Our preliminary data suggest that BIN1 KO decreases proliferation of NPCs. In addition, analyses of calcium imaging recordings show decreased number of active cells although, the active ones show a higher calcium spikes frequency and less synchronization. Furthermore, neuronal activity or PTK2B underexpression impairs the differentiation potential of hiNPCs into neurons. As well, and increased calcium spikes frequency in hiNs. Taken together, our preliminary panel of data suggests that both BIN1 and PTK2B regulate important biological processes involved in neuronal differentiation and electrical maturation. Thus, altered expression of these genes in the AD brain could play a role in neuronal hyperexcitability observed in patients.
Background The BIN1 (Bridging Integrator‐1) gene is the second most important Alzheimer’s disease risk gene and has been associated with synaptic transmission defects in animal models. PTK2B (Protein Tyrosine Kinase 2β) is a Ca2+‐activated non‐receptor tyrosine kinase, also identified by genome‐wide association study (GWAS) as an important AD risk factor, and playing a role in the mouse hippocampal synaptic plasticity. Method In this work, we aimed at studying the possible effects of BIN1 or PTK2B underexpression in the electrical activity taking advantage of human induced pluripotent stem cell (hiPSC)‐derived neurons. To this aim, we are using hiPSCs expressing allelic variants of BIN (BIN1+/+ and BIN1‐/‐) or PTK2B (PTK2B+/+, PTK2B+/‐ and PTK2B ‐/‐). Human induced neural progenitor cells (hiNPCs) are generated from these hiPSCs, which are further differentiated into mature neurons and glia. We evaluated the gene expression, cell type composition of cultures, and neuronal electrical activity using western blot, immunocytochemistry, pharmacological assays, and calcium imaging as a readout of the electrical function. Result Our preliminary data suggest that BIN1 KO decreases proliferation of NPCs. In addition, analyses of calcium imaging recordings show decreased number of active cells although, the active ones show a higher calcium spikes frequency and less synchronization. Furthermore, neuronal activity or PTK2B underexpression impairs the differentiation potential of hiNPCs into neurons. As well, and increased calcium spikes frequency in hiNs. Conclusion Taken together, our preliminary panel of data suggests that both BIN1 and PTK2B regulate important biological processes involved in neuronal differentiation and electrical maturation. Thus, altered expression of these genes in the AD brain could play a role in neuronal hyperexcitability observed in patients.
Author Costa, Marcos Romualdo
Lambert, Jean‐Charles
De Farias, Ana‐Raquel Melo
Saha, Orthis
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Snippet Background The BIN1 (Bridging Integrator‐1) gene is the second most important Alzheimer’s disease risk gene and has been associated with synaptic transmission...
The BIN1 (Bridging Integrator-1) gene is the second most important Alzheimer's disease risk gene and has been associated with synaptic transmission defects in...
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Title Role of the late‐onset Alzheimer’s disease risk genes bin1 and ptk2b in the hyperexcitability of hiPSC‐derived neurons
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