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：
8641971
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/8641971
关键词：
Address Adult Adverse effects Age Age-associated memory impairment Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Precursor Amyloid deposition Behavior Behavioral Biological Process Body Size Body Weight Brain Breeding Chromosome 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 Peptides 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）：淀粉样蛋白异常积累-¿肽 (A¿) 是由淀粉样前体蛋白 (APP) 通过 BACE1 和 β-分泌酶的两次连续蛋白水解裂解产生的，被广泛认为在阿尔茨海默病 (AD) 患者的发展中具有因果作用。 (DS)，由于 APP 位于 21q21 的 21 号染色体有一个额外的拷贝，与年龄相关的认知能力下降和 AD 痴呆比正常人早 30-40 年。一般人群中，他们的大脑总是会形成淀粉样斑块，因为 BACE1 裂解 APP 会引发 A¿ ，抑制 BACE1 活性应减少 A¿ 的形成因此，为了在人类中安全使用 BACE1 抑制剂，充分了解 BACE1 在成人中的生物学功能非常重要。值得注意的是，新生 BACE1 缺失小鼠的体型减小，存活率降低。然而，与年龄匹配的野生型同窝小鼠相比，如果 BACE1 缺失小鼠能够存活到出生后第 10 天，并且 BACE1 缺失小鼠和 BACE1 缺失小鼠之间的体重差异会显着降低。随着时间的推移，野生型小鼠具有生育能力，但确实会出现多种轻度至中度表型，例如癫痫发作、精神分裂症样行为、视网膜病理学、活动依赖性 CA3 突触缺陷的发生率增加。 BACE1 缺失小鼠中的传递、轴突引导缺陷和髓鞘形成受损对 BACE1 缺失小鼠中这些表型的一种可能解释是早期发育缺陷的遗留效应。确定BACE1是否是成年小鼠正常功能所必需的，我们已经生成了条件性BACE1基因敲除小鼠，并将在成年小鼠中删除BACE1，这种新的小鼠模型将使我们能够回答诸如抑制成年小鼠中的BACE1活性是否安全等问题。晚年的 BACE1 抑制是否仍能有效去除先前存在的淀粉样蛋白斑块，该模型也可实用地回答成人中的 BACE1 抑制是否会改善 tau 病理学的问题。控制 BACE1 活性的抑制将对减少或逆转 AD 病理产生最佳效果通过测试我们的假设，我们将针对三个具体目标进行实验：表征 BACE1 条件 KO 小鼠并确定诱导的 BACE1 缺陷是否会导致 AD 病理。目标 2：确定诱导的 BACE1 缺陷是否可以逆转 AD 转基因小鼠大脑中预先形成的淀粉样斑块。图 3：检查 BACE1 抑制是否会影响 Ts65Dn 唐氏综合症小鼠模型的认知功能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，例如成人中 BACE1 的显着减少是否会对减少认知功能产生有益影响。或消除 AD 和 DS 病理。