RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in Alzheimer’s disease

Background: Excessive neuronal activity promotes amyloid-β (Aβ) production in the brain. The Aβ oligomer triggers synaptic degeneration that precedes plaque and tangle pathology. However, the signaling molecules that link Aβ oligomers to synaptic pathology remain unclear. RAPGEF2, a guanine-nucleotide exchange factor for the small GTPase Rap, plays a role in activity-dependent synapse remodeling and is involved in the pathogenesis of epilepsy commonly observed in Alzheimer’s disease (AD) patients and mouse models. Thus, we postulated that the perturbation of the RAPGEF2 signal may contribute to Aβ oligomer-induced synaptopathy in AD. Methods: To investigate the potential role of RAPGEF2 in Aβ oligomer-induced synaptic and cognitive impairments in AD, we utilized a combination of approaches including biochemistry, molecular cell biology, light and electron microscopy, behavioral tests with primary neuron cultures, multiple AD mouse models and postmortem human AD brain tissue. Results: We observed significantly elevated RAPGEF2 levels in the postmortem human AD hippocampus. RAPGEF2 levels also increased in the transgenic AD mouse models, generating high levels of Aβ oligomers before exhibiting synaptic and cognitive impairment. RAPGEF2 upregulation activated its downstream effectors Rap2 and JNK. In cultured hippocampal neurons, oligomeric Aβ treatment increased the fluorescence intensity of RAPGEF2 and reduced the number of dendritic spines, while silencing RAPGEF2 expression blocked Aβ oligomer-induced spine loss. Additionally, the in vivo knockdown of RAPGEF2 expression in the AD hippocampus prevented cognitive deficits and the loss of excitatory synapses. Conclusions: These findings demonstrate that the upregulation of RAPGEF2 levels mediates Aβ oligomer-induced synaptic and cognitive disturbances in the AD hippocampus. We propose that early intervention regarding RAPGEF2 expression may have beneficial effects on early synaptic pathology and memory loss in AD.