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: 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
• 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' 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

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）：淀粉样肽（A¿）的异常积累，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，被广泛认为在阿尔茨海默氏病（AD）的发展中具有因果作用。患有唐氏综合症（DS）的人，由于 APP 位于 21q21 的 21 号染色体有一个额外的拷贝，因此比普通人群早 30-40 年出现与年龄相关的认知能力下降和 AD 痴呆，并且他们的大脑总是会形成淀粉样斑块。由于 BACE1 裂解 APP 会引发 A¿ 的产生，因此抑制 BACE1 活性应该会减少 A¿ 的形成，因此是 AD 的治疗靶点。为了在人体中安全使用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，与年龄匹配的野生型同窝小鼠相比，新生 BACE1 缺失小鼠的体型和存活率均降低。然而，如果 BACE1 缺失小鼠能够存活超过出生后第 10 天，则死亡率会显着降低，并且随着时间的推移，BACE1 缺失和野生型小鼠之间的体重差异会变得更小。在成年中，BACE1缺失小鼠具有生育能力，但确实会出现多种轻度至中度表型，例如BACE1缺失小鼠癫痫发作的发生率增加、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、轴突引导缺陷和髓鞘形成受损。 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。为了确定成年小鼠的正常功能是否需要 BACE1，我们生成了条件性 BACE1 敲除小鼠，并将删除成年小鼠中的 BACE1。这种新的小鼠模型将使我们能够回答诸如抑制成人 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。该模型还可以实用地回答成人中 BACE1 抑制是否会改善 tau 病理学的问题。我们在该提案中的中心假设是，控制 BACE1 活性的抑制将对减少或逆转 AD 病理产生最佳效果。通过检验我们的假设，我们将针对三个特定目标进行实验。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类似的表型变化。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。目标 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或消除 AD 和 DS 病理产生有益的影响。