CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates β-cleavage of β-amyloid precursor protein (APP) through interacting with β-site APP cleaving protein 1 (BACE1)

Accumulation of the neurotoxic β-amyloid (Aβ) peptide in the brain is central to the pathogenesis of Alzheimer disease. Aβ is derived from the β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases, and the production of Aβ is greatly affected by the subcellular localization of these factors. CUTA, the mammalian CutA divalent cation tolerance homolog (E. coli), has been proposed to mediate acetylcholinesterase activity and copper homeostasis, which are important in Alzheimer disease pathology. However, the exact function of CUTA remains largely unclear. Here we show that human CUTA has several variants that differ in their N-terminal length and are separated as heavy (H) and light (L) components. The H component has the longest N terminus and is membrane-associated, whereas the L component is N-terminally truncated at various sites and localized in the cytosol. Importantly, we demonstrate that the H component of CUTA interacts through its N terminus with the transmembrane domain of β-site APP cleaving enzyme 1 (BACE1), the putative β-secretase, mainly in the Golgi/trans-Golgi network. Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1-mediated APP processing/Aβ secretion, respectively. RNA interference of CUTA decelerates intracellular trafficking of BACE1 from the Golgi/trans-Golgi network to the cell surface and reduces the steady-state level of cell surface BACE1. Our results identify the H component of CUTA as a novel BACE1-interacting protein that mediates the intracellular trafficking of BACE1 and the processing of APP to Aβ.     

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

BACE1 is the β-secretase enzyme that initiates production of the β-amyloid peptide involved in Alzheimer disease. However, little is known about the functions of BACE1. BACE1-deficient mice exhibit mild but complex neurological phenotypes suggesting therapeutic BACE1 inhibition may not be completely free of mechanism-based side effects. Recently, we have reported that BACE1 null mice have axon guidance defects in olfactory sensory neuron projections to glomeruli in the olfactory bulb. Here, we show that BACE1 deficiency also causes an axon guidance defect in the hippocampus, a shortened and disorganized infrapyramidal bundle of the mossy fiber projection from the dentate gyrus to CA3. Although we observed that a classical axon guidance molecule, EphA4, was cleaved by BACE1 when co-expressed with BACE1 in HEK293 cells, we could find no evidence of BACE1 processing of EphA4 in the brain. Remarkably, we discovered that the axon guidance defects of BACE1^−/− mice were strikingly similar to those of mice deficient in a recently identified BACE1 substrate, the neural cell adhesion molecule close homolog of L1 (CHL1) that is involved in neurite outgrowth. CHL1 undergoes BACE1-dependent processing in BACE1^+/+, but not BACE1^−/−, hippocampus, and olfactory bulb, indicating that CHL1 is a BACE1 substrate in vivo. Finally, BACE1 and CHL1 co-localize in the terminals of hippocampal mossy fibers, olfactory sensory neuron axons, and growth cones of primary hippocampal neurons. We conclude that BACE1^−/− axon guidance defects are likely the result of abrogated BACE1 processing of CHL1 and that BACE1 deficiency produces a CHL1 loss-of-function phenotype. Our results imply the possibility that axon mis-targeting may occur in adult neurogenic and/or regenerating neurons as a result of chronic BACE1 inhibition and add a note of caution to BACE1 inhibitor development.     

问题解答(1)

问:绿色植物在有阳光时行光合作用吸二氧化碳放出氧气,在晚上没阳光时只有呼吸作用吸氧气放二氧化碳,为什么总说早晨到树林中散步空气好呢? 答:因为空气流动得很厉害,所以在一般树林中白天夜晚O_2及CO_2含量的改变是极小的.说早晨空气好,并不是植物起了什么作用,而是因为夜间人们的活动停止了,车马不在路上奔驰了,工厂的烟囱不冒烟了.加上树林中的湿度较大,尘土都降落在地上,空气就更为清洁了.我们夜间睡在屋中,屋中温度较高,不好气味的有机物(器物中发出或人呼出)空气中也很多,所以一到树林中,凉爽而清洁的空气,眼界的开朗就使我们心神为之一振.(吴相钰、董愚得答)     

Proteomic identification of specifically carbonylated brain proteins in APP(NLh)/APP(NLh) × PS-1(P264L)/PS-1(P264L) human double mutant knock-in mice model of Alzheimer disease as a function of age

Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aβ), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aβ42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the β-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aβ peptides. Aβ has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aβ production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APP (NLh)/APP(NLh) × PS-1(P246L)/PS-1(P246L) human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.     

吊罗山昆虫(1)

1963年12月18日至1964年1月14日,笔者等在海南吊罗山的南喜及小妹林场进行了20多天的昆虫调查,采得昆虫标本一批,共计有15个目120余科。吊罗山位于海南岛东南部陵水县西北,东经104°5＇,北纬23°9＇,最高峰拔海1290米,林木以常绿阔叶林为主。年平均气温24.7℃,年平均降雨量1623.9毫米。我们调查期间正值冬季,所采昆虫标本比夏季的少,但仍有一定代表性。因为当时在广东大陆地区,野外能见到的昆虫为数不多,而陵水县12月份平均气温达20°8C,1月份平均气温19.6℃,在吊罗山林区仍然是“彩蝶纷飞”,调查期间出现的种类,主要是蝶类、直翅目、半翅目、双翅目、     

植物新陈代谢(1)

1　知识点评1.1　把握代谢含义与酶、ATP应用新陈代谢是生物的最基本特征 ,是生物与非生物的根本区别 ,是生物的生长、发育、繁殖、遗传、进化的基础。对于新陈代谢的概念 ,要从性质上、方向上和实质上去理解新陈代谢的概念。从性质上看 ,新陈代谢包含物质代谢和能量代谢两方面内容 ;从方向上看 ,新陈代谢包括同时进行、对立统一的同化作用和异化作用 ;从实质上看 ,新陈代谢的过程就是细胞内的化学反应 ,就是生物体自我更新的过程。酶是活细胞产生的具有催化能力的一类有机物 ,其中绝大多数酶是蛋白质 ,2 0世纪 80年代以来 ,科学家发现少…