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：
9304940
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/9304940
关键词：
Address Adult Adverse effects Age Age-associated memory impairment Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Behavior Behavioral Biological Process Body Size Body Weight Brain Chromosomes, Human, Pair 21 Cleaved cell Clinical Trials Cognitive deficits Death Rate Defect Dementia Development Down Syndrome Doxycycline Elderly Elements Enterobacteria phage P1 Cre recombinase Enzymes Epilepsy Functional disorder General Population Generations Genes Growth Human Impairment Incidence Individual Knockout Mice Knowledge Learning Mediating Membrane Memory Memory impairment Modeling Molecular Mus Neonatal Neuregulin 1 Neurofibrillary Tangles Neurologic Dysfunctions Oral Pathologic Pathology Patients Peptide Vaccines Peptides Phenotype Plasma Production Protein Fragment Reporting Retinal Role Schedule Schizophrenia Seizures Senile Plaques Sodium Channel Survival Rate Synaptic Transmission System Testing Tetanus Helper Peptide Tetracycline Control Therapeutic Time Tissues Transgenic Mice Wild Type Mouse abeta accumulation amyloid formation amyloid peptide axonal guidance base beta-site APP cleaving enzyme 1 cognitive function drug discovery experimental study extracellular functional outcomes gamma secretase human study improved inhibitor/antagonist mouse Ts65Dn mouse model myelination overexpression phase II trial postnatal prevent public health relevance recombinase-mediated cassette exchange small molecule synaptic function tau Proteins therapeutic target voltage

项目摘要

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）：淀粉样蛋白-β 肽 (Aß) 的异常积累，由淀粉样蛋白前体蛋白 (APP) 通过 BACE1 和 γ-分泌酶的两次连续蛋白水解裂解产生，被广泛认为在患有唐氏综合症 (DS) 的个体会因 APP 所在的 21 号染色体的额外拷贝而发生阿尔茨海默病 (AD)。 21q21，与年龄相关的认知能力下降和 AD 痴呆比一般人群早 30-40 年，并且他们的大脑总是会形成淀粉样蛋白斑块，因为 BACE1 裂解 APP 会启动 Aß 的产生，因此抑制 BACE1 活性应该会减少淀粉样蛋白斑块。 Aß 的形成，因此是 AD 的治疗靶点为了在人类中安全使用 BACE1 抑制剂，充分了解 BACE1 在其中的生物学功能非常重要。值得注意的是，与同龄野生型同窝小鼠相比，新生 BACE1 缺失小鼠的体型和存活率均有所下降，但是，如果 BACE1 缺失小鼠能够在出生后第 10 天和出生后存活，则死亡率会显着降低。随着时间的推移，BACE1 缺失小鼠和野生型小鼠之间的体重差异变得更小。 BACE1 缺失小鼠中的癫痫发作、精神分裂症样行为、视网膜病理、活动依赖性 CA3 突触传递缺陷、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的遗留效应。为了确定 BACE1 是否是成年小鼠正常功能所必需的，我们培育了条件性 BACE1 敲除小鼠，并将在成年小鼠中删除 BACE1。小鼠模型将使我们能够回答诸如成人中抑制 BACE1 活性是否安全以及晚年抑制 BACE1 是否仍能有效去除先前存在的淀粉样斑块等问题。该模型也可实用地回答 BACE1 抑制是否有效的问题。我们在这项提议中的中心假设是，控制 BACE1 活性的抑制将对减少或逆转 AD 病理产生最佳效果。目标 1：表征 BACE1 条件性 KO 小鼠，并确定诱导的 BACE1 缺陷是否会导致与 BACE1 缺失小鼠中观察到的表型变化类似。目标 2：确定诱导的 BACE1 缺陷是否可以逆转预先形成的淀粉样斑块。 AD 转基因小鼠大脑。研究 BACE1 抑制是否会影响 Ts65Dn 唐氏综合症小鼠模型的认知功能。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或消除 AD 和 DS 病理产生有益影响。