EIF2α在血管性认知功能障碍与突触可塑性损伤中的作用

Vascular cognitive impairment(VCI) induced by chronic cerebral hypoperfusion is involved in the common pathological feature in Alzheimer’s disease and vascular dementia.But we previously showed that improving hypoperfusion could not entirely reverse cognitive impairment of VCI;chronic cerebral hypoperfusion could lead to synaptic plasticity deficit, and cognitive impairment induced by chronic cerebral hypoperfusion was closely related to synaptic plasticity deficit.As a result,searching and intervening in a key target of synaptic plasticity are an effective way of preventing VCI. Recent discoveries reported in magazines as Nature indicate that eukaryotic initiation factor 2α(eIF2α)plays an important role in synaptic plasticity and Long-term memory formation,and a decreased standard of eIF2α phosphorylation can protect against cerebral ischemic injury.We therefore surmise that eIF2αplays a key role in VCI. Our current study adopts the model of chronic cerebral hypoperfusion to observe the eIF2α phosphorylation impact of VCI,and to study changes of synaptic plasticity mediated by eIF2α by regulating the phosphorylation of eIF2α in cognitive function、ultrastructure、electrophysiology and molecular biology,thereby investigating the role of synaptic plasticity mediated by eIF2αin VCI, which provides a new target and thinking for the treatment of VCI correlate senile dementia,such as Alzheimer’s disease and vascular dementia.

慢性脑低灌注所致的血管性认知功能障碍(VCI)是阿尔茨海默病和血管性痴呆共有的重要病理基础。但我们前期研究发现，改善低灌注并不能完全逆转VCI的认知障碍；慢性脑低灌注大鼠突触可塑性降低，其所致的认知障碍与突触损害密切相关。因此寻找增强突触可塑性的关键靶点进行干预是VCI防治的有效途径。近期Nature等杂志报道真核起始因子2α(eIF2α)对突触可塑性和长期记忆的形成非常关键，并且磷酸化eIF2α水平的下调对缺血性脑损伤起保护作用。因此我们推测eIF2α在VCI中发挥着重要作用。本实验采用慢性脑低灌注模型，观察VCI对eIF2α磷酸化的影响,并通过干预eIF2α磷酸化水平，从认知功能、超微结构、电生理到分子生物学等手段多角度研究eIF2α介导的突触可塑性改变，研究eIF2α介导的突触可塑性机制在VCI中的作用，为阿尔茨海默病和血管性痴呆等VCI相关的老年期痴呆防治提供新的靶点和思路.

慢性脑低灌注(chronic cerebral hypoperfusion, CCH)可导致认知功能的损害。但改善低灌注并不能完全逆转认知功能损伤。我们前期研究发现慢性脑低灌注大鼠所致的认知功能损害与突触损害密切相关，且真核起始因子2α(eIF2α)对突触可塑性和长期记忆的形成非常关键。为了进一步研究eIF2α在慢性脑低灌注所致的血管性认知功能障碍(VCI)中的作用，我们研究了VCI对eIF2α磷酸化的影响，并通过干预eIF2α磷酸化水平观察eIF2α介导的突触可塑性改变。本实验发现（1）CCH组大鼠的p-eIF2α的表达与假手术组比较明显上升，而给予eIF2α激酶抑制剂干预后CCH+PERKI组和CCH+PKRI组的p-eIF2α的表达与CCH组比较则明显下降。（2）通过行为学实验发现eIF2α激酶抑制剂可以改善CCH所导致的大鼠空间学习记忆功能的损害。（3）CCH可导致突触相关蛋白MAP-2和突触素的表达下降，而eIF2α激酶抑制剂可对CCH诱导的MAP-2和突触素的下降起到改善作用。（4）eIF2α激酶抑制剂能够减轻CCH所导致的LTP的损害。因此我们认为eIF2α介导的突触可塑性机制在慢性脑低灌注所致认知功能损害中起关键性作用，eIF2α磷酸化下调对慢性脑低灌注所致认知功能损害起改善作用。