Accumulation of amyloid beta (Aβ) soluble forms in the cerebral parenchyma is the mainstream concept underlying memory deficit in the early phase of Alzheimer’s disease (AD). PKMζ plays a critical role in the maintenance of long-term memory. Yet, the role of this brain-specific enzyme has not been addressed in AD. We examined the impact of hippocampal PKMζ overexpression on AD-related memory impairment in rats. Oligomeric form of Aβ (oAβ) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats under stereotaxic surgery. One week later, 2 μl of lentiviral vector (10⁸ T.U. / ml.) encoding PKMζ genome was microinjected into the dorsal hippocampus. Seven days later, behavioral performance was assessed using shuttle box and Morris water maze. The expression levels of GluA1, GluA2 and KCC2 were determined in the hippocampus using western blot technique. Our data showed that oAβ impairs both passive avoidance and spatial learning and memory. However, overexpression of PKMζ in the dorsal hippocampus restored the behavioral performance. This improving effect was blocked by microinjection of ZIP, a PKMζ inhibitor, into the hippocampus. oAβ or PKMζ did not significantly change GluA1 level in the hippocampus. Furthermore, PKMζ failed to restore elevated KCC2 level induced by oAβ. However, oAβ decreased GluA2 level, and overexpression of PKMζ restored its expression toward the control level. In conclusion, hippocampal overexpression of PKMζ restored memory dysfunction induced by amyloidopathy in part, through preserving hippocampal GluA2 containing AMPA receptors. PKMζ’s signaling pathway could be considered as a therapeutic target to battle memory deficits in the early phase of AD.

脑实质中淀粉样蛋白 β (Aβ) 可溶性形式的积累是阿尔茨海默病 (AD) 早期阶段记忆缺陷的主流概念。PKMζ 在维持长期记忆方面起着关键作用。然而，这种大脑特异性酶的作用尚未在 AD 中得到解决。我们检查了海马 PKMζ 过表达对大鼠 AD 相关记忆障碍的影响。在立体定向手术下，将寡聚形式的 Aβ (oAβ) 或载体双侧显微注射到雄性 Wistar 大鼠的背侧海马中。一周后，2 μl 慢病毒载体（10 ⁸TU / ml.) 编码 PKMζ 基因组被显微注射到背海马体中。7 天后，使用穿梭箱和莫里斯水迷宫评估行为表现。使用蛋白质印迹技术测定海马中GluA1、GluA2和KCC2的表达水平。我们的数据显示 oAβ 会损害被动回避和空间学习和记忆。然而，背侧海马中 PKMζ 的过表达恢复了行为表现。这种改善效果被 ZIP（一种 PKMζ 抑制剂）显微注射到海马体中所阻断。oAβ 或 PKMζ 没有显着改变海马中的 GluA1 水平。此外，PKMζ 未能恢复由 oAβ 诱导的升高的 KCC2 水平。然而，oAβ 降低了 GluA2 水平，而 PKMζ 的过表达使其表达恢复到对照水平。综上所述，PKMζ 的海马过表达通过保留含有 AMPA 受体的海马 GluA2 部分恢复了由淀粉样变引起的记忆功能障碍。PKMζ 的信号通路可被视为对抗 AD 早期记忆缺陷的治疗靶点。