Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1).
Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1).
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DOI：
10.1523/jneurosci.3588-11.2011
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发表时间：
2011-11-02
期刊：
影响因子：
--
通讯作者：
Tsai LH
中科院分区：
文献类型：
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作者：
Giusti-Rodríguez P;Gao J;Gräff J;Rei D;Soda T;Tsai LH
阿尔茨海默病（Alzheimer's disease，AD）是痴呆的最常见病因，其特征是记忆力减退、认知能力下降、淀粉样蛋白β（amyloid β，Aβ）蓄积和进行性神经退行性变。Cdk 5是一种脯氨酸导向的丝氨酸/苏氨酸激酶，其被p25蛋白激活涉及许多神经退行性疾病。CK-p25诱导型小鼠模型表现出进行性神经元死亡、Aβ升高、突触可塑性降低和前脑神经元中p25过表达后学习受损。CK-p25小鼠的Aβ水平以及淀粉样前体蛋白（APP）加工酶β-分泌酶（BACE 1）也增加。目前尚不清楚Aβ增加在CK-p25小鼠的认知和神经退行性表型中起什么作用。在目前的工作中，我们通过BACE 1的部分遗传缺失将CK-p25小鼠中的Aβ水平恢复到野生型小鼠的水平，使我们能够检查该小鼠模型的Aβ非依赖性表型。我们发现，在CK-p25小鼠中，Aβ水平的正常化导致突触和认知缺陷的拯救。相反，神经元丢失没有改善。我们的研究结果表明，在CK-p25小鼠中，p25/Cdk 5活性的增加可能通过Aβ依赖性途径介导认知和突触损伤。这些发现探索了靶向Aβ产生在神经变性和认知障碍小鼠模型中的影响，以及这如何转化为散发性AD的治疗方法。
Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the amyloid precursor protein (APP) processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wildtype mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.