RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer's disease

Amyloid-β (Aβ) oligomers trigger synaptic degeneration that precedes plaque and tangle pathology. However, the signalling molecules that link Aβ oligomers to synaptic pathology remain unclear. Here, we addressed the potential role of RAPGEF2 as a novel signalling molecule in Aβ oligomer-induced synaptic and cognitive impairments in human-mutant amyloid precursor protein (APP) mouse models of Alzheimer's disease (AD).

These findings demonstrate that the upregulation of RAPGEF2 levels mediates Aβ oligomer-induced synaptic and cognitive disturbances in the AD hippocampus. We propose that an early intervention regarding RAPGEF2 expression may have beneficial effects on early synaptic pathology and memory loss in AD.

To investigate the role of RAPGEF2 in Aβ oligomer-induced synaptic and cognitive impairments, we utilised a combination of approaches including biochemistry, molecular cell biology, light and electron microscopy, behavioural tests with primary neuron cultures, multiple AD mouse models and post-mortem human AD brain tissue.

We found significantly elevated RAPGEF2 levels in the post-mortem 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 the 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 and the intensities of synaptic marker proteins, while silencing RAPGEF2 expression blocked Aβ oligomer-induced synapse 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 an early intervention regarding RAPGEF2 expression may have beneficial effects on early synaptic pathology and memory loss in AD.