Inhibition of BACE1 for benefiting Alzheimer's patients

抑制 BACE1 可使阿尔茨海默病患者受益

基本信息

批准号：
8741927
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
项目类别：
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/8741927
关键词：
Address Adult Adverse effects Age Age-associated memory impairment Alzheimer&apos s Disease 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 Human Incidence Individual Knockout Mice Knowledge Lead Learning Mediating Membrane Memory Memory impairment Modeling Molecular Mus Neonatal Neuregulin 1 Neurofibrillary Tangles Neurologic Pathology Patients Phase II Clinical Trials Phenotype Plasma Production Protein Fragment Reporting Retinal Role Schedule Schizophrenia Seizures Senile Plaques Sodium Channel Staging Survival Rate Synaptic Transmission System Technology Testing Tetanus Helper Peptide Tetracycline Control Therapeutic Time Tissues Transgenic Mice Vaccines Wild Type Mouse Work amyloid peptide axonal guidance base beta-site APP cleaving enzyme 1 cognitive function drug discovery extracellular functional outcomes human study improved inhibitor/antagonist mouse Ts65Dn mouse model myelination overexpression peptide A postnatal prevent public health relevance recombinase research study secretase small molecule synaptic function tau Proteins therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): Abnormal accumulation of amyloid-¿ peptide (A¿), which is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and ?-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 A¿, inhibition of BACE1 activity should decrease the formation of A¿ 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）：淀粉样蛋白的异常积累肽（a¿）是由淀粉样蛋白前体蛋白（APP）通过BACE1和分泌酶进行的两个序列蛋白质裂解而产生的，该蛋白质蛋白质（AD）在阿尔茨海默氏病（AD）的发展中具有因果关系（DS）。），由于染色体21的额外副本，该应用程序位于21q21 lier，其大脑自从BACE1启动A swavage of App swavage。，抑制BACE1活性应减少A的形成并且是人类的hibitor的安全UFE，它是成年人的tounc tounc tounc tounc tounc tounc ，如果Bace1-null小鼠弯曲到第10天，并且随着时间的推移，Bace1-Null和野生型小鼠之间的体重差异要小得多，那么死亡率是显着的。在癫痫发作中，精神分裂症的行为，视网膜病理学，活动依赖性CA3突触传播中的缺陷，轴突指导中的缺陷和骨髓损伤以确定是否需要bace1-null小鼠。在成年小鼠中，我们已经产生了有条件的Bace1敲除小鼠，并且在小鼠中删除了小鼠Mousel Willolow的Bace1，并且Bace1 Inhiber Vate是否仍将删除先前存在的淀粉样杆菌。对成年人的BACE1抑制是否会改善TAU病理学。我们在此提案中的中心假设是，对BACE1活性的受控抑制作用将通过测试我们的假设来减少或逆转AD病理。目标1：表征Bace1特征KO小鼠，并确定诱导的Bace1缺乏症是否会类似于Bace1-Null小鼠中观察到的一些典型变化。我的鼠标模型。