RAPGEF2 mediates oligomeric Aβ‐induced synaptic loss and cognitive dysfunction in the 3xTg‐AD mouse model

출처 : Neuropathology and Applied Neurobiology
등록일 : 2020-12-20
조회 : 59

<div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">원제목: RAPGEF2 mediates oligomeric Aβ‐induced synaptic loss and cognitive dysfunction in the 3xTg‐AD mouse model of Alzheimer’s disease</span></div><div style="text-align: justify;" align="justify"><br></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">*Aims</span></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">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).</span></div><div style="text-align: justify;" align="justify"><br></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">*Methods</span></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">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.</span></div><div style="text-align: justify;" align="justify"><br></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">*Results</span></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">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.</span></div><div style="text-align: justify;" align="justify"><br></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">*Conclusions</span></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">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.</span></div><div style="text-align: justify;" align="justify"><br></div><div style="text-align: justify; line-height: 1.8;" align="justify"><span style="font-size: 11pt;">[참고] 연합뉴스,<a href="https://www.yna.co.kr/view/AKR20210118062200053" target="_blank"> "한국뇌연구원, 알츠하이머병 시냅스 손상 유발 기전 규명"</a>, (2021.01.18)</span></div><div><br></div>

URL : https://onlinelibrary.wiley.com/doi/10.1111/nan.12686

태그 : #건강 #퇴행성뇌신경질환 #알츠하이머성 치매 #치매 #알츠하이머 #시냅스 #신경세포 #RAPGEF2 #단백질 #RAP2 #JNK #아밀로이드 베타 #사회문제 #사회문제해결 #사회문제해결플랫폼