ApoE4 also had a detrimental effect on GABAergic neurons in hiPSC-derived neuronal cultures. This was especially true in relatively pure GABAergic neuronal cultures derived from hiPSCs and is consistent with observations in human apoE4 knock-in mouse brains48–51. Hyperphosphorylated tau was accumulated in axons of GABAergic neurons, leading to axonal degeneration, and also mislocalized to neuronal dendrites, as seen in AD brains. These effects, too, were apoE4-specific, as they were abolished by conversion of apoE4 to apoE3. GABAergic interneuron loss and neuronal hyperactivity due to loss of inhibitory tone have been observed in apoE4 knock-in mice48,49,52. Importantly, GABAergic interneuron deficits in apoE4 knock-in mice correlate with spatial learning and memory impairment48,49, and deletion of the apoE4 gene in GABAergic interneurons in LoxP-floxed apoE4 knock-in mice restores normal learning and memory and rescues apoE4-induced impairment of hippocampal network activity53,54. Thus, apoE4-induced GABAergic interneuron degeneration/dysfunction could contribute significantly to dementia in AD patients.
