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β-Amyloid (1-40) TFA 是阿尔茨海默症患者脑斑块中发现的一种主要蛋白片段。

β-Amyloid (1-40) TFA is a primary protein in plaques found in the brains of patients with Alzheimer's disease.

发现β淀粉样蛋白（1-40）表现出神经营养和神经毒性作用，这取决于神经元年龄和β蛋白浓度。

beta-Amyloid (1-40) found to exhibit both neurotrophic and neurotoxic effects that depend on neuronal age and beta-protein concentration.

淀粉样β肽（Aβ）是一种神经营养因子，参与阿尔茨海默病的致病机制。这种药物通过与分泌酶结合来抑制Aβ的产生。已经表明，Aβ与转运蛋白结合并转运到细胞中，并在细胞质中积累。Aβ的生理水平受称为“基因伴侣”的蛋白质调节，该蛋白质可防止Aβ聚集成斑块。硫酸葡聚糖通过与淀粉样蛋白结合并防止其在细胞质中积累来抑制这一过程。通过结构分析，抑制细胞摄取和分泌以及抑制原纤维化，已显示淀粉样β肽三氟乙酸盐（ATFX）抑制Aβ的产生。ATFX还具有作为阿尔茨海默病生物标志物的潜力，因为它可以在尿液或血清中以低浓度检测到

Amyloid beta peptide (Aβ) is a neurotrophic factor that is involved in the pathogenic mechanism of Alzheimer\s disease. This drug inhibits the production of Aβ by binding to the enzyme, secretase. It has been shown that Aβ binds to a transporter protein and is transported into cells, where it accumulates in the cytoplasm. The physiological levels of Aβ are regulated by proteins called "gene chaperones" which prevent Aβ from aggregating into plaques. Dextran sulfate inhibits this process by binding to amyloid and preventing it from accumulating in the cytoplasm. Amyloid beta peptide trifluoroxalate (ATFX) has been shown to inhibit the production of Aβ with structural analysis, inhibition of cellular uptake and secretion, and inhibition of fibrillization. ATFX also has potential as a biomarker for Alzheimer\s disease because it can be detected at low concentrations in urine or serum

“淀粉样β蛋白（Aβ）是一种源自淀粉样前体蛋白（APP）的肽。Aβ是阿尔茨海默病患者大脑中发现的淀粉样斑块的主要成分。它已被证明是LRP1和LRP2的配体，这两种受体参与APP的清除。淀粉样β蛋白（Aβ）是细胞膜离子通道的激活剂，可影响几种离子通道的活性，包括高压激活钾通道和低压激活钙通道。”

"Amyloid beta-protein (Aβ) is a peptide that is derived from amyloid precursor protein (APP). Aβ is the main component of amyloid plaques which are found in the brains of people with Alzheimers disease. It has been shown to be a ligand for LRP1 and LRP2, two receptors involved in the clearance of APP. Amyloid beta-protein (Aβ) is an activator of ion channels in cell membranes and can affect the activity of several types of ion channels, including high-voltage activated potassium channels and low-voltage activated calcium channels."

“淀粉样β蛋白（Aβ）是一种肽，据信在阿尔茨海默病的发展中起着重要作用。Aβ由淀粉样前体蛋白的蛋白水解切割产生，并释放到细胞外空间，在那里它可以与其他细胞相互作用。该蛋白已被证明可以激活离子通道并抑制细胞增殖。它还与细胞上的受体结合，从而导致下游效应，例如抑制配体结合和激活G蛋白偶联受体信号通路。”

"Amyloid beta-protein (Aβ) is a peptide that is believed to play an important role in the development of Alzheimers disease. Aβ is produced by proteolytic cleavage from the amyloid precursor protein and is released into the extracellular space, where it can interact with other cells. The protein has been shown to activate ion channels and inhibit cell proliferation. It also binds to receptors on cells, which leads to downstream effects such as inhibition of ligand binding and activation of G-protein coupled receptor signaling pathways."

β- 淀粉样蛋白（1-40）是研究最广泛的全长多肽，以形成富含 β- 折叠的聚集体著称。其疏水核心驱动原纤维形成与膜相互作用，是研究寡聚化通路的关键材料。主要用于结构生物物理、聚集机制与多肽工程研究。

Beta-Amyloid (1-40) is a widely studied full-length peptide known for forming β-sheet-rich aggregates. Its hydrophobic core drives fibrillization and membrane interactions. The peptide is essential for examining oligomerization pathways. Applications include structural biophysics, aggregation mechanistics, and peptide-engineering research.

Amyloid β-peptide (1-40)是阿尔茨海默病患者脑斑块中发现的主要蛋白质。根据神经年龄以及β-protein的浓度，Amyloid β-peptide (1-40)在向神经以及神经毒素方面都显示出了作用。在Alzheimers disease患者的脑脊髓液中，Amyloid β-peptide (1-40)和Amyloid β-peptide (1-42)也被用来检测amyloid β-蛋白的聚集度。
 

淀粉肽背景：β淀粉样蛋白（Aβ或Abeta）是从淀粉样前体蛋白加工而成的含有36–43个氨基酸的多肽。Aβ是与阿尔兹海默病相关的淀粉样蛋白斑的成分。已有证据表明，Aβ是一个多功能肽，具有显著的非病理性活性。Aβ是阿尔兹海默病患者脑中发现的沉积物的主要成分。在散发性阿尔兹海默病患者的脑中，Aβ的水平升高，造成脑血管病变和神经毒性。Aβ蛋白是由β和γ分泌酶的连续作用而产生的。γ分泌酶产生Aβ肽的C末端，在APP的转膜结构域切割，可以产生许多36-43个氨基酸残基长度的异构体，最常见的异构体是Aβ40和Aβ42。更长形式的Aβ在内质网中切割产生，而更短形式的Aβ在反面高尔基网中产生。

structure of Amyloid β-Peptide (1-40) (human)

淀粉样蛋白肽的 定义淀粉样蛋白 是丝状蛋白质沉积物，大小从纳米到微米不等，并且由肽β链的平行或反平行排列形成的聚集的肽β折叠构成。

结构特征：使用固态NMR（SSNMR），与计算能量最小化过程结合，Tycko和合作者已经提出从淀粉状蛋白肽SS（Aß1-40）的40个残基的形式形成的淀粉样蛋白原纤维的结构在pH 7.4和24 o C在静止条件下。在这种结构中，每个Aß1-40分子在原纤维的核心区域贡献一对ß链，大约跨越残基12-24和30-40。这些由回路25-29连接的链不是同一张ß-sheet的一部分，但参与同一原丝内两个不同的ß-sheets的形成。不同的Aß分子2、3至少从第9到39位残基以平行排列和对齐的方式相互堆叠。通过调用其他实验约束，例如使用透射电子显微镜（TEM）观察到的原丝直径和单位质量通过扫描透射电子显微镜（STEM）1、2测得的长度表明，单个原丝是由四个ß片组成的，它们之间的距离约为10Å。

作用模式：阿尔茨海默氏病（AD）是淀粉样蛋白丝状沉积物的结果，淀粉状蛋白沉积物在分子水平上定义该疾病，发生在神经周膜，轴突，树突和神经元末端，如神经原纤维缠结（NFT），在细胞外神经纤维中淀粉样斑块（APC），以及周围的血管称为淀粉样嗜血性血管病（ACA）。淀粉样蛋白沉积物显然发生在发展NFT的神经元末端区域。已经表明，APC和ACA的主要成分已被证明是4.5kDa的淀粉样蛋白，最初被称为“β-蛋白”或“淀粉样蛋白A4”，我们现在将其称为“βA4”。

功能：钙失调和膜破坏是可溶性淀粉样蛋白低聚物普遍存在的神经毒性机制：进行了一项研究，以研究Ca 2+信号转导可能参与淀粉样蛋白诱导的细胞毒性，疾病相关淀粉样蛋白（β，病毒，胰岛淀粉样蛋白）的均质制剂制备了处于各种聚集状态的多肽，聚谷氨酰胺和溶菌酶），并测试了它们对加载fluo-3的SH-SY5Y细胞的作用。寡聚形式的所有淀粉样蛋白的应用（0.6-6 µg / ml）迅速（约5 s）使细胞内Ca 2+升高，而等量的单体和原纤维则没有。细胞内Ca 2+耗尽后，Abeta42低聚物引起的Ca 2+信号持续存在店，和小信号仍留在钙2 + -游离介质，指示从细胞外和细胞内Ca贡献2+源。膜对Ca 2+的渗透性增加不能归因于内源性Ca 2+通道的活化，因为反应不受强力的Ca 2 +-通道阻滞剂钴的影响。取而代之的是，观察到Abeta42和其他低聚物引起阴离子荧光染料的快速细胞泄漏，这表明膜通透性普遍提高。导致的离子和分子通量失调可能为许多淀粉样变性疾病中Ca 2+失调提供了由低聚物介导的毒性的常见机制。离子起着至关重要的作用，因为它们的跨膜浓度梯度很强，并且参与了细胞功能障碍和死亡。

2型糖尿病中的胰岛淀粉样蛋白和毒性低聚物假说： 2型糖尿病（T2DM）的特征是胰岛素抵抗，胰岛素分泌缺陷，β细胞量减少，β细胞凋亡增加和胰岛淀粉样蛋白。胰岛淀粉样蛋白源自胰岛淀粉样蛋白多肽（IAPP，胰岛淀粉样多肽），该蛋白是通过胰β细胞与胰岛素共表达和共分泌的蛋白。与其他淀粉样蛋白一样，IAPP具有形成膜渗透性毒性低聚物的倾向。越来越多的证据表明，这些有毒的寡聚体而不是这些蛋白质的细胞外淀粉样蛋白形式，是导致神经退行性疾病中神经元丢失的原因。有人提出，胞内IAPP寡聚物的形成可能会导致T2DM 6中的β细胞丢失。

Extracellular amyloid-β peptide deposition into cerebellar plaques and formation of intracellular neurofibrillary fibers accompanied by the loss of neurons are characteristic histopathological lesions found in the brains of Alzheimer‘s disease patients. Individuals suffering from this disease show a gradual loss of cognitive functions and disturbances in behavior. Apart from some rare familial forms of the disease, the onset of Alzheimer‘s disease is usually above 60 years. Since the risk to develop the disease increases with age, Alzheimer‘s disease has turned into a major health and social problem in “first world” countries with an increasing proportion of older people, and is going to become one in emerging states. In this brochure we present amyloid peptides and related products for Alzheimer‘s disease research.

ALZHEIMER’S DISEASE
Alzheimer‘s disease (AD) is the prevalent cause of dementia in elderly people and has become one of the leading causes of death in developed countries together with cardiovascular disorders, cancer, and stroke. It is estimated that more than 46 millions of people suffer from AD all over the world. As age advances, the risk for developing AD increases. The frequency of AD at the age of 60-64 is about 1% and doubles approximately every five years. By the age of 90 and older, approximately 50% of the population suffers from this disease. AD is an irreversible and progressive neurodegenerative disorder. Symptoms include gradual loss of cognitive functions such as memory, verbal and visuospatial abilities, changes in personality, behavior, and activities of daily living. AD patients in the final stages are completely dependent on the care of others.

The characteristic lesions in the brains of AD patients were first described by the German neuropsychiatrist Alois Alzheimer in 1906 during the post-mortem examination of a mentally ill patient whose deterioration he had observed until her death. The lesions consisted of dense extracellular deposits, now designated as neuritic or senile plaques, and intracellular dense bundles of fibrils, which are now known as neurofibrillary tangles.

Currently, diagnosis of AD with adequate testing is approximately 90% accurate. It is based on the exclusion of a variety of diseases causing similar symptoms and a careful neurological and psychiatric examination, as well as neuropsychological testing. Imaging technologies for detecting amyloid plaques and tangles in vivo are becoming more precise and thus a valuable additional tool. Numerous potential biomarkers as α1 -antitrypsin, complement factor H, α2 -macroglobulin, apolipoprotein J, and apolipoprotein A-I for diagnosing AD are being evaluated. However, post-mortem histopathological examination of the brain is still the only definite diagnosis of this disease.

AD can be either inherited or sporadic. The inherited or familial AD is rare and comprises only 5-10% of all cases. Autosomal dominant mutations in the amyloid β/A4 protein precursor (APP) gene on chromosome 21 and the presenilin-1 or -2 genes on chromosomes 14 and 1, respectively, have been attributed to the early onset (before the age of 65) of this disease.

APP belongs to the type-1 integral membrane glycoproteins with at least 10 isoforms generated by alternative splicing of the 19 exons. The predominant transcripts are APP695, APP751, and APP770. A number of mutations within the APP gene have been detected in families with an inherited risk for early onset of AD. Usually, they are named after the region, in which they have been detected, e.g. the London APP717 mutations (V717I, V717F, V717G), the Swedish APP670/671 double mutation (K670N/M671L), the Flemish APP692 mutation (A692G), or the Dutch APP693 mutation (E693Q). The Swedish mutation of the β-secretase cleavage site of APP and mutations of positions 692-694 (Aβ 21-23), which strongly influence the aggregation behavior of Aβ, have been studied intensively.

A choice of relevant mutations in the Aβ region of APP is assembled in the table below.

The presenilins are another group of proteins involved in the development of AD. Presenilins are integral membrane proteins with eight transmembrane domains localized in the endoplasmic reticulum and the Golgi apparatus. A multitude of mutations within the presenilin-1 and two within the presenilin-2 gene account for most of the cases of early onset of AD.

Genetic factors may contribute as well to the late onset of AD. Increased susceptibility is associated with the expression of different apolipoprotein E (ApoE) isoforms due to the polymorphism in the APOE gene on chromosome 19. In the central nervous system, ApoE has been implicated in growth and repair during development or after injury. Carriers of the APOEε4 allele show a higher risk in developing the disease than carriers of the other two possible alleles APOEε2 and APOEε3. The ApoEε4 effect seems to be dose-dependent since individuals with two of these alleles seem to be at two-fold higher risk to develop the disease than those with one allele. Polymorphisms of the α2 -macroglobulin gene on chromosome 12 and the gene coding low-density lipoprotein receptor-related protein 1 (LRP1), LRP1-C/T, have also been suggested to be a risk factor for the late onset of AD. However, further studies in this field are required.

A number of additional, most diverse risk factors have been proposed. These include gender, ethnic group, head trauma, cardiovascular diseases, and educational level.

AD THERAPEUTIC STRATEGIES RELY ON DETAILED KNOWLEDGE OF THE MOLECULES INVOLVED

Women, Hispanics, individuals who have experienced a head trauma earlier in life, and persons who suffer from cardiovascular diseases appear to have a higher risk of developing the disease.

The etiology of AD is still not completely understood. Initial research focused upon determining the molecular structure of the senile plaques and the neurofibrillary tangles originally described by Alois Alzheimer. The main constituents of the senile plaques were identified as cleavage products of APP, designated as amyloid β-peptides (Aβ peptides).

Depending on the composition and the fraction of fibrillar to non-fibrillar forms of these amyloid peptides, several kinds of senile plaques can be distinguished. Three types of proteases, α-secretase, β-secretase (or β-site APP-cleaving enzyme, BACE), and γ-secretase are involved in APP processing. APP can either be processed by the α- and γ- or by the β- and γ-secretases. The major two amyloid peptides identified in senile plaques, amyloid β-protein (1-40) (Aβ40) and amyloid β-protein (1-42) (Aβ42), are generated by successive proteolysis of APP by β- and γ-secretases. Cleavage of APP by β-secretase results in the release of the extracellular N-terminal protein fragment known as soluble APP-β molecule (sAPP-β). Then, the membrane-retained APP is further processed within the transmembrane domain by γ-secretase to yield either Aβ40 or Aβ42. The formation of Aβ40 and Aβ42 is a normal process, and both peptides can be detected in the plasma and cerebrospinal fluid (CSF) of healthy subjects.

In most studies, similar concentrations of Aβ40 have been measured in the CSF of both healthy controls and AD patients. On the other hand, Aβ42 concentrations in the CSF of AD patients are significantly lower than in normal controls, probably reflecting an increased deposition as insoluble plaques.

The neurofibrillary tangles found inside neurons of Alzheimer’s brains are composed of paired helical filaments whose main components are hyperphosphorylated forms of tau, a microtubule associated protein involved in promoting microtubule assembly and stabilization. Self-assembly into paired helical filaments is believed to be a result of hyperphosphorylation due to either the increased activity of protein kinases or the decreased activity of phosphatases.

Several lines of evidence support the view that the accumulation of Aβ42 in the brain is a primary event in the development of AD. Increased cerebral Aβ production appears to be characteristic for all the mutations within the APP and the presenilin genes of familial AD. In patients with Down syndrome (trisomy 21), elevated levels of APP and Aβ due to a third copy of the APP gene result in deposition of Aβ at an early age between 20 and 30.

Formation of neurofibrillary tangles is considered as a consequence of Aβ deposition with a further impact on the progression of the disease possibly due to disruption of axonal transport mechanisms in neurons.

The detailed knowledge about the molecules involved in AD has led to the development of several therapeutic strategies.

One strategy aims at the reduction of Aβ40 and Aβ42 by inhibition of either β- or γ-secretase activity or by clearance of Aβ in the brain by means of immunization with these peptides. Transition metals as Cu, Fe and Zn play an important role in the pathology of AD. Aggregation and neurotoxicity of Aβ are dependent on the presence of copper, so Cu-chelating agents showed promising effects in animal models. Another approach is the prevention of the cellular inflammatory response in the cerebral cortex elicited by the progressive accumulation of Aβ. Further preventive therapeutic strategies are based on the findings that cholesterol-lowering drugs such as statins and estrogen replacement therapy reduce the risk of developing AD. An additional treatment alternative would be the inhibition of the serine-threonine protein kinases, glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (CDK5), which are probably responsible for the phosphorylation of the tau protein. Inhibition of calpain, an enzyme showing increased activity in AD brains, led to promising results in animal studies. Calpain cleaves the CDK5 activator p35 leading to p25 formation and CDK5 overactivation.

Several acetylcholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine have been approved for the treatment of mild to moderate AD by the FDA and other authorities. They act by reducing the deficits of the neurotransmitter acetylcholine associated with cognitive impairment in AD patients. The amantadine derivative memantine, an NMDA receptor antagonist, which was already used for the treatment of moderate to severe AD in Europe, has gained approval in the United States by the FDA as well.

A promising drug candidate, the β-secretase inhibitor verubecestat (MK-8931) developed for the management of mild to moderate AD, has moved to phase III. Moreover, the BACE inhibitor AZD3293 showed encouraging results in clinical studies. Antibodies as aducanumab and solanezumab, which have been designed to degrade plaques and lower the level of Aβ in the brain, have reached advanced stages of clinical testing for mild cases of AD.

Despite the many promising therapeutic approaches, AD still remains a major burden for the patients, their relatives, and the society.