Inhibition of BACE1 for benefiting Alzheimer's patients

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产生的淀粉样蛋白-β肽（AAPs）的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21号染色体的额外拷贝，其中APP位于21q21，比普通人群早30 - 40年发生与年龄相关的认知衰退和AD痴呆，并且他们的大脑不变地发展淀粉样斑块。由于BACE1对APP的切割启动了Ablation的产生，因此BACE1活性的抑制应减少Ablation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，新生BACE1基因敲除小鼠与其年龄匹配的野生型同窝出生小鼠相比，体型和存活率降低。然而，如果BACE1缺失小鼠可以存活超过出生后第10天，则死亡率显著降低，并且随着时间的推移，BACE1缺失小鼠和野生型小鼠之间的体重差异变得小得多。在成年时，BACE1基因敲除小鼠是可生育的，但确实发展出多种轻度至中度表型，如癫痫发作、精神分裂症样行为、视网膜病理学、活性依赖性CA3突触传递缺陷、轴突导向缺陷和BACE1基因敲除小鼠髓鞘形成受损的发生率增加。BACE1基因敲除小鼠中这些表型的一个潜在解释是早期发育缺陷的遗留效应。为了确定BACE1是否是成年小鼠正常功能所必需的，我们已经产生了条件性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一些问题，例如在成年人中抑制BACE1活性是否安全，以及在老年人中抑制BACE1是否仍然有效地去除预先存在的淀粉样斑块。该模型也将实用于回答成人中BACE1抑制是否会改善tau病理学的问题。我们在这个提议中的中心假设是，BACE1活性的受控抑制将对减少或逆转AD病理具有最佳效果。通过检验我们的假设，我们将在三个具体目标进行实验。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表型变化相似的表型变化。目的2：确定诱导的BACE1缺陷是否可以逆转AD转基因小鼠脑中预先形成的淀粉样斑块。目的3：检查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病理产生有益影响。

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.