Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?

被引:303
作者
Adlard, Paul A. [1 ,2 ]
Parncutt, Jacqui M. [1 ]
Finkelstein, David I. [1 ]
Bush, Ashley I. [1 ,2 ]
机构
[1] Mental Hlth Res Inst, Oxidat Biol Lab, Parkville, Vic 3052, Australia
[2] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia
基金
澳大利亚研究理事会; 英国医学研究理事会;
关键词
PROTEIN TRANSGENIC MICE; TARGETING A-BETA; MOUSE-BRAIN; VESICLES; ZNT3; RECEPTOR; PLAQUES; RAT; ACTIVATION; EXPRESSION;
D O I
10.1523/JNEUROSCI.5255-09.2010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn2+ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (-46%; p < 0.01); the postsynaptic protein PSD95 (-37%; p < 0.01); the glutamate receptors AMPAR (-34%; p < 0.01), NMDAR2a (-64%; p < 0.001), and NMDAR2b (-49%; p < 0.05); the surrogate marker of neurogenesis doublecortin (-31%; p < 0.001); and elements of the BDNF pathway, pro-BDNF (-30%; p < 0.05) and TrkB (-22%; p < 0.01). In addition, there is a concomitant decrease in neuronal spine density (-6%; p < 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (-50%; p < 0.01) in healthy older humans (ages, 48-91 years; r(2) = 0.47; p = 0.00019) and particularly in Alzheimer's disease (AD) (-36%; p < 0.0001). Thus, age-dependent loss of transsynaptic Zn2+ movement leads to cognitive loss, and since extracellular beta-amyloid is aggregated by and traps this pool of Zn2+, the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.
引用
收藏
页码:1631 / 1636
页数:6
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