PTEN recruitment controls synaptic and cognitive function in Alzheimer's models
PTEN recruitment controls synaptic and cognitive function in Alzheimer's models
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DOI：
10.1038/nn.4225
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发表时间：
2016-03-01
影响因子：
25
通讯作者：
Esteban, Jose A.
中科院分区：
文献类型：
--
作者：
Knafo, Shira;Sanchez-Puelles, Cristina;Esteban, Jose A.
淀粉样β肽（A β）的稳态异常是导致阿尔茨海默病中从轻度损伤到完全痴呆的认知缺陷的突触功能障碍的原因。β似乎使突触可塑性事件偏向抑郁。我们发现，抑制PTEN（一种对长期抑郁症至关重要的脂质磷酸酶）可以挽救阿尔茨海默病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模仿和阻断Ab诱导的抑郁症的突触抑制。从机制上讲，Ab触发PTEN的PDZ依赖性募集进入突触后区室。使用缺乏PDZ基序的PTEN敲入小鼠和细胞可渗透的干扰肽，我们发现这种机制对于Ab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关于Ab诱导的突触功能障碍的分子机制的基本信息，并可能提供新的基于机制的治疗靶点来抵消下游Ab信号传导。
Dyshomeostasis of amyloid-beta peptide (A beta) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. A beta 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 Ab-induced depression. Mechanistically, Ab 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 Ab-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Ab-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Ab signaling.