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：
8878977
负责人：
RIQIANG YAN
金额：
$ 31.52万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878977
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 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 Technology 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 human study improved inhibitor/antagonist mouse Ts65Dn mouse model myelination overexpression phase II trial postnatal prevent 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-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（通过应用程序证明）：淀粉样蛋白肽（Aß）GH的异常积累，通过Bace1和γ-分泌酶进行两种顺序蛋白质裂解，被广泛认为是在阿尔茨海默氏病的发展中具有因果关系的作用。相关的认知能力下降和AD痴呆症比一般人群提前30 - 40年，而develoid斑块则降低了CE1活动。与年龄匹配的野生窝窝相比，它不可或缺地了解成人新生儿Bace1-null小鼠的生物学功能，并且生存率与年龄匹配的野生型相比。可以超越产后第10天的生存，并且随着时间的流逝，Bace1-nul L和野生型小鼠之间的体重差异，Bace1-Null小鼠肥沃，但确实会发展出多种轻度至中度的表型。精神分裂症的行为依赖于VITY的CA3突触传播。鼠标。这种新的鼠标模型将使我们回答诸如成人的白色抑制性抑制作用之类的问题，安全的sather bace1抑制作用仍将刺激淀粉样蛋白斑块。我们的中心假设在控制BACE1活动的情况下会具有最佳的效果或通过测试我们的假设来逆转AD。 BACE1对表型的变化相似的Tose1-null小鼠2：确定ED BACE1缺乏是否可以反向AD转基因小鼠大脑中的预先形成的淀粉样蛋白斑。 BACE1在成人福利效应中减少或消除AD和DS病理的效果。