Work

SGK1 inhibition restores excitability of cortical neurons derived from Alzheimer's disease patients

Year: 2026

Type: article

Abstract: The vast majority of Alzheimer's disease (AD) cases are sporadic, without a clear etiology. We have previously found increased expression of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) in mouse models of dementia, postmortem cortical tissues and induced pluripotent stem cells (iPSCs)-derived cortical neurons from patients with sporadic AD (sAD). SGK1 is induced by a variety of cellular stress. The physiological consequences of elevated SGK1 in sAD is unclear. Here, we differentiated iPSCs from four sAD patients and four age- and sex-matched healthy controls into electrophysiologically mature cortical neurons with prolonged culture for more than 100 days. The sAD cortical neurons exhibited significant reductions in voltage-gated Na + currents, amplitudes of evoked action potentials, and frequencies of spontaneous excitatory postsynaptic currents and spontaneous action potentials. Application of a selective inhibitor of SGK1 reversed all these phenotypes in sAD neurons without affecting control neurons. The SGK1-dependent hypoexcitability suggests that a convergent and inborn mechanism attenuates neuronal communications despite different genetic background of the sAD patients. Their iPSC-derived cortical neurons have captured the defective neurotransmission, which underlies cognitive and memory symptoms of AD, many decades before clinical manifestations. The study offers a new pathway to restore synaptic transmission in AD. • Mature iPSC-derived cortical neurons from AD patients and healthy controls. • Reduced Na + currents and evoked action potential overshoot in AD neurons. • Decreased frequencies of spontaneous EPSC and spontaneous AP in AD neurons. • Hypoexcitability of AD neurons rescued by SGK1 inhibition. • SGK1-dependent inborn hypoexcitability in AD is captured in iPSC-derived neurons.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2026.107345

Authors: Zhongjiao Jiang, Komal Saleem, Emily Fisher, Li Li, Zhen Yan, Jian Feng

Institution: University at Buffalo, State University of New York

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,180