BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice.
BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice.
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DOI：
10.1523/eneuro.0067-18.2018
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发表时间：
2018-07
期刊：
影响因子：
3.4
通讯作者：
Tanzi RE
中科院分区：
文献类型：
--
作者：
Chatila ZK;Kim E;Berlé C;Bylykbashi E;Rompala A;Oram MK;Gupta D;Kwak SS;Kim YH;Kim DY;Choi SH;Tanzi RE
β-淀粉样前体蛋白裂解酶1（β-Site amyloid precursor protein cleaving enzyme 1，BACE 1）是β-淀粉样蛋白（β-amyloid，Aβ）产生所必需的，是阿尔茨海默病（Alzheimer's disease，AD）的主要致病分子之一，因此BACE 1正被积极用作AD的药物靶点。成人海马神经发生（AHN）是一个终生的过程，已知对学习和记忆很重要，并可能具有再生受损神经组织的潜力。在这项研究中，我们研究了BACE 1是否调节AHN，这对它作为AD药物靶点的适用性具有重要意义。向2月龄野生型（BACE 1 +/+）、杂合型和纯合型BACE 1敲除小鼠（分别为BACE 1 +/-和BACE 1-/-）的队列注射5-溴-2 ′-脱氧尿苷（BrdU），并在1天后处死，以检查BACE 1缺失对成年脑中神经前体细胞（NPC）增殖的影响。在BrdU注射后4周处死平行组小鼠，以确定BACE 1对新生NPC存活和分化的影响。我们发现，与BACE 1 +/+小鼠相比，BACE 1-/-小鼠的NPC增殖增加，而不同基因型的NPC存活率无差异。在BACE 1-/-小鼠中，NPC向神经元谱系的分化受损。然而，没有观察到不同基因型的星形胶质细胞，未成熟神经元的比例，或少突胶质细胞的生产。重要的是，与在替代细胞命运中不存在互补增加的情况下神经元分化的减少相对应，发现与BACE 1 +/+和BACE 1 +/-小鼠相比，BACE 1-/-小鼠在海马中具有未分化的NPC池。
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer’s disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1+/+), heterozygous, and homozygous BACE1 knockout mice (BACE1+/– and BACE1–/–, respectively) were injected with 5-bromo-2′-deoxyuridine (BrdU) and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiation of newborn NPCs. We found that NPC proliferation was increased in BACE1–/– mice compared to BACE1+/+ mice, while no difference was observed in NPC survival across genotypes. Differentiation of NPCs to neuronal lineage was impaired in BACE1–/– mice. However, no differences were observed in astrogenesis, the proportion of immature neurons, or the production of oligodendrocytes across genotypes. Importantly, corresponding with a decrease in neuronal differentiation in the absence of a complementary increase in an alternate cell fate, BACE1–/– mice were found to have a pool of undifferentiated NPCs in the hippocampus compared to BACE1+/+ and BACE1+/– mice.