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: 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
• 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' 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; 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; 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

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（由应用提供）：淀粉样蛋白肽（A a）的异常积累，它是由淀粉样蛋白前体蛋白（APP）通过Bace1和secretase通过两个顺序蛋白水解裂解产生的，被广泛认为是在Alzheimer病（AD）发展中具有因果关系。患有唐氏综合症（DS）的个体，由于APP位于21 Q21的21染色体副本，与一般人群相比，与年龄相关的认知能力下降和AD痴呆症的发展，其大脑不断发展淀粉样蛋白斑块。由于BACE1对APP进行切割会启动a的产生，因此BACE1活性的抑制应减少A的形成，因此是AD的治疗靶标。为了安全地使用人类的BACE1抑制剂，充分了解成年人Bace1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仔相比，新生儿Bace1-null小鼠的身体大小和存活率降低。但是，如果Bace1-Null小鼠能够在产后第10天以后生存，并且体重的差异随着时间的流逝而显着降低，并且随着时间的推移，Bace1-Null和野生型小鼠之间的体重差异变得较小。在成年人中，BACE1-NULL小鼠肥沃，但确实会发展出多种轻度至中度的表型，例如癫痫发作的发生率增加，精神分裂症样行为，残留病理学，定义了依赖于CA3的CA3合成透射，缺陷，轴突引导和乳液中的肌电损伤中的骨髓中的骨髓骨值。 Bace1-Null小鼠中这些表型的一种潜在解释是早期发育缺陷的结转作用。为了确定成年小鼠正常功能是否需要BACE1，我们已经产生了有条件的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抑制成人Bace1活性的问题，并且后来的BACE1抑制是否仍将有效地消除固定质斑块。该模型也将是实用的，以回答成年人BACE1抑制是否会改善TAU病理的问题。我们在该提案中的中心假设是，对BACE1活性的控制抑制作用将对减少或逆转AD病理产生最佳影响。通过检验我们的假设，我们将以三个特定目的进行实验。目标1：表征BACE1条件KO小鼠并确定诱导的Bace1缺乏是否会导致表型变化，类似于Bace1-Null小鼠中观察到的变化。目标2：确定诱导的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块。目标3：检查BACE1抑制是否会影响TS65DN唐氏综合征小鼠模型中的认知功能。从这项研究中获得的知识将使我们能够回答许多未满足的问题，例如，成年人中Bace1的大幅降低是否会对减少或消除AD和DS病理学产生有益的影响。