Savonenko A V, Melnikova T, Laird F M, Stewart K-A, Price D L, Wong P C
Departments of Pathology, Neurology, and Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5585-90. doi: 10.1073/pnas.0710373105. Epub 2008 Apr 2.
beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.
β-位点淀粉样前体蛋白裂解酶1（BACE1）是淀粉样β前体蛋白（APP）倒数第二步裂解所必需的，该裂解导致淀粉样β肽的产生，而这是阿尔茨海默病发病机制的核心。除了在APP的内蛋白水解中发挥作用外，BACE1还参与神经调节蛋白1（NRG1）的蛋白水解过程，并影响中枢和外周轴突的髓鞘形成。尽管NRG1在基因上与精神分裂症有关，且NRG1(+/-)小鼠表现出许多精神分裂症样行为特征，但尚不清楚BACE1依赖性NRG1信号的改变是否会导致类似的行为异常。为了验证这一假设，我们分析了NRG1加工受损的BACE1(-/-)小鼠中被认为是精神分裂症临床特征啮齿动物类似物的行为。我们证明，BACE1(-/-)小鼠在预脉冲抑制、新奇诱导的多动、对谷氨酸能精神兴奋剂（MK-801）的超敏反应、认知障碍和社交识别缺陷方面存在缺陷。重要的是，其中一些表现对非典型抗精神病药物氯氮平的治疗有反应。此外，尽管NRG1的受体ErbB4的总量没有变化，但在BACE1(-/-)小鼠的大脑中，ErbB4与突触后致密蛋白95（PSD95）的结合显著减少。与ErbB4在脊柱形态和突触功能中的作用一致，BACE1(-/-)小鼠海马锥体神经元的脊柱密度降低。总体而言，我们的研究结果表明，BACE1依赖性NRG1/ErbB4信号的改变可能参与了精神分裂症和相关精神疾病的发病机制。
