Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.

临床研究表明，一些老年人的大脑中积聚了大量组织病理学上的阿尔茨海默氏病（AD）病变，但并未出现痴呆症的迹象。AD的动物模型代表了识别可能促进认知弹性的基因的合适工具，因此，本研究首先着手确定老年Tg2576小鼠模型中具有认知弹性的个体。对这些小鼠进行的转录组分析鉴定出PLA2G4E为可能赋予痴呆抵抗力的基因。实际上，在晚期AD患者的大脑中PLA2G4E的显着降低是明显的，而在患有AD神经病理性病变但没有痴呆迹象的早期患者中未观察到这种变化。我们证明，腺相关病毒载体介导的海马神经元PLA2G4E的过度表达完全恢复了老年APP / PS1小鼠的认知功能障碍，而没有影响淀粉样蛋白或tau病理学。这些PLA2G4E过表达的APP / PS1小鼠比假注射的小鼠发育出更多的树突棘，这与观察到的认知能力改善相吻合。因此，这些结果支持以下观点：PLA2G4E的丧失可能在AD痴呆症发作中起关键作用，突显了PLA2G4E过表达作为治疗AD和其他伴随记忆缺陷的疾病的新型治疗策略的潜力。这些PLA2G4E过表达的APP / PS1小鼠比假注射的小鼠发育出更多的树突棘，这与观察到的认知能力改善相吻合。因此，这些结果支持以下观点：PLA2G4E的丧失可能在AD痴呆症发作中起关键作用，突显了PLA2G4E过表达作为治疗AD和其他伴随记忆缺陷的疾病的新型治疗策略的潜力。这些PLA2G4E过表达的APP / PS1小鼠比假注射的小鼠发育出更多的树突棘，这与观察到的认知能力改善相吻合。因此，这些结果支持以下观点：PLA2G4E的丧失可能在AD痴呆症发作中起关键作用，突显了PLA2G4E过表达作为治疗AD和其他伴随记忆缺陷的疾病的新型治疗策略的潜力。