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而产生的淀粉样蛋白- β肽（asβ）异常积累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APP位于21q21的21号染色体的额外拷贝，比一般人群早30-40年出现与年龄相关的认知能力下降和AD痴呆，并且他们的大脑不变地出现淀粉样斑块。由于BACE1对APP的切割启动了asas的产生，抑制BACE1的活性应该会减少asas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，充分了解成人BACE1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幼崽相比，新生的bace1缺失小鼠的体型和存活率都降低了。然而，如果bace1缺失小鼠能够存活超过出生后第10天，那么死亡率将显著降低，并且随着时间的推移，bace1缺失小鼠与野生型小鼠之间的体重差异将大大缩小。在成年小鼠中，bace1缺失小鼠是可生育的，但确实会出现多种轻度至中度表型，如癫痫发作发生率增加、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bace1缺失小鼠的髓鞘形成受损。对bace1缺失小鼠中这些表型的一个潜在解释是早期发育缺陷的传递效应。为了确定成年小鼠的正常功能是否需要BACE1，我们产生了条件BACE1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在成人中抑制BACE1活性是否安全以及老年BACE1抑制是否仍然有效去除先前存在的淀粉样斑块等问题。该模型对于回答成人BACE1抑制是否会改善tau病理的问题也将是实用的。我们的中心假设是，控制BACE1活性的抑制将对减少或逆转AD病理具有最佳效果。为了验证我们的假设，我们将在三个特定的目标中进行实验。目的1：表征BACE1条件下的KO小鼠，并确定诱导的BACE1缺乏是否会导致与BACE1缺失小鼠相似的表型变化。目的2：确定诱导的BACE1缺乏是否可以逆转AD转基因小鼠大脑中预先形成的淀粉样斑块。目的3：研究BACE1抑制是否会影响Ts65Dn唐氏综合征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尚未解决的问题，例如成人中BACE1的显著减少是否会对减少或消除AD和DS病理有有益的影响。