Increased MANF expression contributes to synaptic dysfunctions in Alzheimer disease

The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. In this study, we found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA binding protein 2 (ELAVL2), and affects its binding to RNA transcripts that are involved in synaptic functions. Reducing MANF expression ameliorates the synaptic pathology in the hippocampus of AD mice. Together, our study established MANF as a mechanistic link between ER stress and synaptic dysfunctions in AD and hinted at MANF as a therapeutic target in AD treatment.

内质网（endoplasmic reticulum, ER）应激激活是阿尔茨海默病（Alzheimer disease, AD）大脑的早期病理标志性特征，但ER应激如何促进AD的发生与发展，目前仍未得到充分阐释。中脑星形胶质细胞源性神经营养因子（Mesencephalic astrocyte-derived neurotrophic factor, MANF）是一类非经典神经营养因子，同时也是ER应激诱导蛋白。本研究发现，MANF的表达上调与AD模型小鼠海马体的突触丢失呈显著相关。通过转基因或病毒载体方法在小鼠体内异位表达MANF，可引发突触丢失以及学习记忆功能缺陷。本研究还证实，MANF可与ELAV样RNA结合蛋白2（ELAV like RNA binding protein 2, ELAVL2）相互作用，并影响其与突触功能相关RNA转录本的结合。降低MANF的表达水平可缓解AD模型小鼠海马体的突触病理损伤。综上，本研究确立了MANF作为ER应激与AD突触功能障碍之间的机制性联系，并提示MANF可作为AD治疗的潜在治疗靶点。