Reduced TrkB and BACE1 Elevation: Potential Link in Alzheimer's Pathogenesis

TrkB 和 BACE1 升高降低：阿尔茨海默病发病机制中的潜在联系

• 批准号: 8665366
• 负责人: MASUO OHNO
• 金额: $ 8.06万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665366
• 关键词: Acceleration; Address; Age; Age-Months; Agonist; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Cerebrospinal Fluid; Cleaved cell; Data; Defect; Dementia; Deterioration; Disease; Disease Progression; Elderly; Enzymes; Event; Functional disorder; Gene Delivery; Generations; Genetic; Genetic Transcription; Human; Impaired cognition; Impairment; Injection of therapeutic agent; Knockout Mice; Lead; Link; Mediating; Mediator of activation protein; Memory; Memory impairment; Molecular; Mus; Neuronal Plasticity; Neurons; Pathogenesis; Pathway interactions; Phase; Phenotype; Phosphotransferases; Play; Process; Production; Proteins; Reporting; Research; Role; Senile Plaques; Signal Pathway; Signal Transduction; Site; Specificity; Staging; Stem cell transplant; Synapses; Syncope; Testing; Therapeutic Intervention; Transgenic Mice; Transgenic Model; Translations; Tropomyosin; Up-Regulation; Wild Type Mouse; amyloid pathology; beta-site APP cleaving enzyme 1; brain cell; functional restoration; in vivo; mild cognitive impairment; mimetics; mouse model; nerve stem cell; neuronal survival; neurotoxicity; neurotrophic factor; normal aging; peptide A; public health relevance; receptor; secretase; small molecule

DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play a crucial role in neuronal plasticity and survival. Increasing evidence suggests that deficient BDNF-TrkB signaling may mediate amyloid- (?)-induced neurotoxicity, synaptic dysfunction and memory deficits in Alzheimer's disease (AD). However, it has not been examined whether BDNF-TrkB dysfunction may also contribute to pathogenic mechanisms upstream to A? accumulation. Interestingly, our recent study demonstrated that the selective TrkB agonist 7,8-dihydroxyflavone not only restores impaired memory and TrkB signaling but also lowers A? levels by reducing the ?-secretase enzyme BACE1 in a mouse model of AD. In this R03 application, we will test our focused hypothesis that reduction in TrkB signaling, which is found in early AD or its harbinger mild cognitive impairment (MCI), may be responsible for inducing BACE1 elevation and consequently initiating and/or accelerating disease processes. Specifically, we will use (i) pharmacological (ANA-12, a selective and blood-brain barrier permeable TrkB antagonist) and (ii) genetic (TrkB haploinsufficiency) approaches to experimentally reproduce the impairment of TrkB signaling associated with MCI or incipient AD. In Aim 1-1, these approaches will be applied to young 5XFAD transgenic mice, which develop little or only faint amyloid pathology and are still normal in memory function. We will first compare the levels of BACE1 expression in ANA-12-treated 5XFAD or TrkB+/-.5XFAD bigenic mice (3-month old) with those of age-matched 5XFAD control mice. We will then explore the molecular mechanisms by which pharmacological and genetic reduction of TrkB signaling may cause BACE1 elevation (e.g., changes in transcription, translation, protein stability) and exacerbate AD-like phenotypes including memory deficits in these 5XFAD mice. In Aim 1-2, we will further test whether administration of ANA-12 or TrkB haploinsufficiency may be sufficient to upregulate BACE1 in wild-type mice. Given that A?42 may be important for increasing BACE1 expression in neurons around amyloid plaques during the progression of AD, it will be critical to determine a causal relationship between reduced TrkB signaling and BACE1 elevation in wild- type controls that completely lack toxic human A? species. If the data is positive, we will examine whether the same mechanisms as found in 5XFAD mice may mediate BACE1 elevation following impaired TrkB signaling in wild-type mice, regardless of the presence of human A?. Together, the proposed research is expected to address a key question whether deficient BDNF-TrkB signaling may not only be a mediator of memory impairments as a consequence of A? accumulation (as shown by previous studies) but also have a crucial role in initiating or accelerating the AD process via BACE1 elevation.

描述(申请人提供)：脑源性神经营养因子(BDNF)及其受体原肌球蛋白相关激酶B(TrkB)在神经元的可塑性和存活中起着至关重要的作用。越来越多的证据表明，BDNF-TrkB信号缺陷可能介导了淀粉样蛋白诱导的神经毒性、突触功能障碍和阿尔茨海默病(AD)的记忆障碍。然而，目前还没有研究BDNF-TrkB功能障碍是否也与A上游的致病机制有关？积累。有趣的是，我们最近的研究表明，选择性TrkB激动剂7，8-二羟基黄酮不仅可以恢复受损的记忆和TrkB信号，还可以降低A？通过降低阿尔茨海默病小鼠模型中β-分泌酶BACE1的水平。在R03的应用中，我们将测试我们的重点假设，即在AD早期发现的TrkB信号减少或其轻度认知障碍(MCI)可能导致BACE1升高，从而启动和/或加速疾病过程。具体地说，我们将使用(I)药理学方法(ANA-12，一种选择性的血脑屏障通透性TrkB拮抗剂)和(Ii)遗传方法(TrkB单倍体功能不全)来实验复制与MCI或早期AD相关的TrkB信号损害。在目标1-1中，这些方法将应用于年轻的5XFAD转基因小鼠，这些小鼠很少或只出现微弱的淀粉样变性，并且记忆功能仍然正常。我们将首先比较ANA-12处理的5XFAD或TrkB+/-.5XFAD双基因小鼠(3月龄)与年龄匹配的5XFAD对照组小鼠的BACE1表达水平。然后，我们将探索TrkB信号的药物和遗传减少可能导致BACE1升高的分子机制(例如，转录、翻译、蛋白质稳定性的变化)，并加剧这些5XFAD小鼠的AD样表型，包括记忆障碍。在目标1-2中，我们将进一步测试ANA-12或TrkB单倍体不足是否足以上调野生型小鼠的BACE1。鉴于A？42可能在AD进展过程中增加淀粉样斑块周围神经元中BACE1的表达，因此在完全缺乏毒性人类A？物种。如果数据是阳性的，我们将检查在5XFAD小鼠中发现的相同机制是否可能在野生型小鼠TrkB信号受损后介导BACE1升高，而不考虑人类A？的存在。总之，这项拟议的研究有望解决一个关键问题，即BDNF-TrkB信号缺陷是否不仅是A？BACE1的积累不仅在启动或加速AD过程中起着关键作用，而且通过BACE1的升高也起到了关键作用。