Inhibition of BACE1 for benefiting Alzheimer's patients

抑制 BACE1 可使阿尔茨海默病患者受益

• 批准号: 9111767
• 负责人: RIQIANG YAN
• 金额: $ 32.49万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111767
• 关键词: Address; Adult; Adverse effects; Age; Age-associated memory impairment; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Behavior; Behavioral; Biological Process; Body Size; Body Weight; Brain; Breeding; Chromosomes, Human, Pair 21; Cleaved cell; Clinical Trials; Cognitive deficits; Death Rate; Defect; Dementia; Development; Down Syndrome; Doxycycline; Elderly; Elements; Enzymes; Epilepsy; Functional disorder; General Population; Generations; Genes; Growth; Health; Human; Incidence; Individual; Knockout Mice; Knowledge; Lead; Learning; Mediating; Membrane; Memory; Memory impairment; Modeling; Molecular; Mus; Neonatal; Neuregulin 1; Neurofibrillary Tangles; Neurologic Dysfunctions; Pathology; Patients; Peptide Vaccines; Peptides; Phenotype; Plasma; Production; Protein Fragment; Reporting; Retinal; Role; Schedule; Schizophrenia; Seizures; Senile Plaques; Sodium Channel; Staging; Survival Rate; Synaptic Transmission; System; Testing; Tetanus Helper Peptide; Tetracycline Control; Therapeutic; Time; Tissues; Transgenic Mice; Wild Type Mouse; Work; amyloid formation; amyloid peptide; axonal guidance; base; beta-site APP cleaving enzyme 1; cognitive function; drug discovery; extracellular; functional outcomes; gamma secretase; human study; improved; inhibitor/antagonist; mouse Ts65Dn; mouse model; myelination; overexpression; phase II trial; postnatal; prevent; recombinase; recombinase-mediated cassette exchange; research study; small molecule; synaptic function; tau Proteins; therapeutic target; voltage

DESCRIPTION (provided by applicant): Abnormal accumulation of amyloid-ß peptide (Aß), which is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and γ-secretase, is widely regarded as having a causal role in the development of Alzheimer's disease (AD). Individuals with Down syndrome (DS), due to an extra copy of chromosome 21 in which APP is located at 21q21, develop age-related cognitive decline and AD dementia by 30-40 years earlier than in the general population, and their brains invariantly develop amyloid plaques. Since cleavage of APP by BACE1 initiates the production of Aß, inhibition of BACE1 activity should decrease the formation of Aß and is therefore a therapeutic target for AD. For the safe use of BACE1 inhibitors in humans, it is very important to fully understand the biological functions of BACE1 in the adult. Notably, neonatal BACE1-null mice have reduced body sizes and survival rates when compared to their age-matched wild-type littermates. However, the death rate is significantly decreased if BACE1-null mice can survive beyond postnatal day 10 and the differences in body weight become much smaller between BACE1-null and wild-type mice over time. In the adult, BACE1-null mice are fertile but do develop multiple mild to moderate phenotypes such as increases in the incidence of epileptic seizures, schizophrenia-like behaviors, retinal pathology, deficits in activity-dependent CA3 synaptic transmission, defects in axonal guidance and impaired myelination in BACE1-null mice. One potential explanation for these phenotypes in BACE1-null mice is the carryover effect from early developmental defects. To determine whether BACE1 is required for normal functions in adult mice, we have generated conditional BACE1 knockout mice and will delete BACE1 in the adult mouse. This new mouse model will allow us to answer questions such as whether inhibition of BACE1 activity in adult is safe and whether BACE1 inhibition at late ages will still e effective in removing preexisting amyloid plaques. This model will also be practical to answer the question of whether BACE1 inhibition in the adult will ameliorate tau pathology. Our central hypothesis in this proposal is that controlled inhibition of BACE1 activity will have optimal effecs on reducing or reversing AD pathologies. By testing our hypothesis, we will perform experiments in three specific aims. Aim 1: To characterize BACE1 conditional KO mice and to determine whether induced BACE1 deficiency will lead to phenotypic changes similar to those observed in BACE1-null mice. Aim 2: To determine whether induced BACE1 deficiency can reverse pre-formed amyloid plaques in AD transgenic mouse brains. Aim 3: to examine whether BACE1 inhibition will impact cognitive function in the Ts65Dn Down syndrome mouse model. The knowledge gained from this study will allow us to answer many unmet questions such as whether a significant reduction of BACE1 in the adult would have beneficial effects for reducing or eliminating AD and DS pathologies.

描述(由申请人提供)：淀粉样前体蛋白(APP)通过BACE1和γ-分泌酶连续两次蛋白分解而产生的淀粉样多肽(A？)异常积聚，被广泛认为在阿尔茨海默病(AD)的发展中具有因果作用。唐氏综合征(DS)患者由于额外的21号染色体拷贝(APP位于21q21)，比普通人群提前30-40年患上与年龄相关的认知能力下降和AD痴呆，他们的大脑总是出现淀粉样斑块。由于BACE1对APP的切割启动了A？的产生，抑制BACE1的活性应该会减少A？的形成，因此是AD的治疗靶点。为了在人体内安全使用BACE1抑制剂，充分了解BACE1在成人体内的生物学功能是非常重要的。值得注意的是，与年龄匹配的野生型小鼠相比，新生的BACE1缺失小鼠的身体尺寸和存活率都有所减小。然而，如果BACE1基因缺失的小鼠可以存活到出生后第10天以上，并且随着时间的推移，BACE1基因缺失小鼠和野生型小鼠之间的体重差异变得小得多，死亡率就会显著降低。在成年后，BACE1基因缺失的小鼠可以生育，但也会发展出多种轻到中度的表型，如癫痫发作的发生率增加，精神分裂样行为，视网膜病理，活动依赖的CA3突触传递缺陷，轴突引导缺陷和BACE1基因缺失小鼠的髓鞘形成障碍。BACE1基因缺失小鼠的这些表型的一个潜在解释是早期发育缺陷的遗留效应。为了确定成年小鼠的正常功能是否需要BACE1，我们培育了有条件的BACE1基因敲除小鼠，并将删除成年小鼠的BACE1。这个新的小鼠模型将允许我们回答这样的问题，例如在成人中抑制BACE1活性是否安全，以及在晚年抑制BACE1是否仍然有效地消除先前存在的淀粉样斑块。该模型也可用于回答在成人中抑制BACE1是否会改善tau病理的问题。我们在这项建议中的中心假设是，控制抑制BACE1活性将在减少或逆转AD病理方面具有最佳效果。通过检验我们的假设，我们将在三个具体目标上进行实验。目的1：研究BACE1条件性KO小鼠的生物学特性，并确定BACE1缺陷是否会导致与BACE1基因缺失小鼠相似的表型改变。目的：探讨诱导BACE1缺乏症能否逆转AD转基因小鼠脑内预先形成的淀粉样斑块。目的：检测BACE1抑制对Ts65Down综合征小鼠认知功能的影响。从这项研究中获得的知识将使我们能够回答许多未解决的问题，例如成年人BACE1的显著减少是否会对减少或消除AD和DS的病理产生有益的影响。