Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
Unidad de Biofísica CSIC-UPV/EHU, Campus Universidad del País Vasco, Leioa, Spain.
Nat Neurosci. 2016 Mar;19(3):443-53. doi: 10.1038/nn.4225. Epub 2016 Jan 18.
Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.
淀粉样β肽（Aβ）的代谢失衡是导致阿尔茨海默病患者从轻度认知障碍到全面痴呆的突触功能障碍的原因。Aβ似乎使突触可塑性事件向抑郁倾斜。我们发现，抑制 PTEN（一种对长时程抑郁至关重要的脂质磷酸酶）可挽救阿尔茨海默病的细胞和动物模型中的正常突触功能和认知。相反，过表达 PTEN 的转基因小鼠表现出类似于 Aβ诱导的抑郁的突触抑制。从机制上讲，Aβ触发 PDZ 依赖性将 PTEN 募集到突触后隔室。使用缺乏 PDZ 基序的 PTEN 敲入小鼠和细胞渗透性干扰肽，我们发现该机制对于 Aβ诱导的突触毒性和认知功能障碍至关重要。我们的研究结果提供了有关 Aβ诱导的突触功能障碍的分子机制的基本信息，并且可能为对抗下游 Aβ信号提供新的基于机制的治疗靶标。
