Klotho overexpression protects human cortical neurons from β-amyloid induced neuronal toxicity
<p dir="ltr">Klotho, a well-known aging suppressor protein, has been implicated in neuroprotection and the regulation of neuronal senescence. While previous studies have demonstrated its anti-aging properties in human brain organoids, its potential to mitigate neurodegenerative proce...
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2025
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| Summary: | <p dir="ltr">Klotho, a well-known aging suppressor protein, has been implicated in neuroprotection and the regulation of neuronal senescence. While previous studies have demonstrated its anti-aging properties in human brain organoids, its potential to mitigate neurodegenerative processes triggered by β-amyloid remains underexplored. In this study, we utilised human induced pluripotent stem cells (iPSCs) engineered with a doxycycline-inducible system to overexpress <i>KLOTHO</i> and generated 2D cortical neuron cultures from these cells. These neurons were next exposed to pre-aggregated β-amyloid 1–42 oligomers to model the neurotoxicity associated with Alzheimer’s disease. Our data reveal that upregulation of <i>KLOTHO</i> significantly reduced β-amyloid-induced neuronal degeneration and apoptosis, as evidenced by decreased cleaved caspase-3 expression and preservation of axonal integrity. Additionally, <i>KLOTHO</i> overexpression prevented the loss of dendritic branching and mitigated reductions in axonal diameter, hallmark features of neurodegenerative pathology. These results highlight Klotho’s protective role against β-amyloid-induced neurotoxicity in human cortical neurons and suggest that its age-related decline may contribute to neurodegenerative diseases such as Alzheimer’s disease. Our findings underscore the therapeutic potential of Klotho-based interventions in mitigating age-associated neurodegenerative processes.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular Brain<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s13041-025-01199-6" target="_blank">https://dx.doi.org/10.1186/s13041-025-01199-6</a></p> |
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