Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondrial fragmentation and dysfunction are critical pathological features of AD. Chloride intracellular channel 4 (CLIC4) is involved in neuronal apoptosis and regulates mitochondrial functions. Glial maturation factor β (GMFβ) inhibits mitochondrial DNA replication and energy metabolism, causes mitochondrial dysfunction, and regulates apoptosis. Dynamic related protein 1 (DRP1), a key protein in mitochondrial division, exhibits increased activity when its Ser616 site is phosphorylated. However, the role of CLIC4 in Aβ-induced cognitive impairment through the modulation of GMFβ and p-DRP1 (Ser616) to induce mitochondrial dysfunction remains unclear. This study examined the role of CLIC4 in Aβ-induced cognitive impairment in AD mice, focusing on its regulation of GMFβ and p-DRP1 (Ser616) and the subsequent effects on mitochondrial hyperfission and dysfunction. Our findings demonstrate that overexpression of CLIC4 in the mouse hippocampus or in HT22 cells resulted in pathological changes analogous to those observed following Aβ exposure. These changes include elevated levels of GMFβ and p-DRP1 (Ser616) proteins, mitochondrial fission, and increased intracellular ROS production. Conversely, CLIC4 knockdown mitigated Aβ-induced neuronal damage. These findings indicate that CLIC4 may be crucial in Aβ-induced hippocampal neurological damage in mice by regulating GMFβ and DRP1 phosphorylation.