Misfolded amyloid-beta conformational variants(strains)as drivers of Alzheimer's disease neuropathology

Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.

Corrigendum: Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

In the article titled“Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease”published on pages 2467-2479,Issue 11,Volume 19 of Neural Regeneration Research(Tang et al.,2024),there are some errors in selecting the appropriate images in Figure 7 by authors during assembling the images.

Medin synergized with vascular amyloid-beta deposits accelerates cognitive decline in Alzheimer's disease:a potential biomarker

Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.

Smart electrochemical sensing of amyloid-beta to manage total Alzheimer's diseases

Need for Alzheimer's disease progression monitoring:Alzheimer's disease(AD)is an irreversible progressive brain disorder that causes severe and incurable neuro-impairment.The World Health Organization estimates that 55 million people are affected by AD dementia by 2020 which may exceed 78 million by 2030 and 139 in 2050.The estimated cost to manage AD is above US$1.3 trillion,which will further increase to US$2.8 trillion by 2030.

Role of peripheral amyloid-β aggregates in Alzheimer’s disease: mechanistic, diagnostic, and therapeutic implications

Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.

Design and redesign journey of a drug for transthyretin amyloidosis

The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).

Anti-amyloid antibodies in Alzheimer’s disease: what did clinical trials teach us?

Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event causing the pathology.However,that conclusion could be only partly true,and there is conflicting evidence about the role of both proteins in AD,being able to precede and influence one another.Some researchers argue that these proteins are mere executors rather than primary causes of pathology.Therefore,there have been continuing refinements of both hypotheses,with alternative explanations proposed.Aβand tau proteins may be independently involved in specific neurotoxic pathways;yet there may be other crucial processes going on in early AD.Moreover,accumulating evidence suggests that Aβand tau act synergistically,rather than additively in disease onset(Jeremic et al.,2021,2023a).

Beyond neurodegeneration:engineering amyloids for biocatalysis

Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet structure.The formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases,such as Alzheimer’s disease,Parkinson’s disease,type-2 diabetes,or amyotrophic lateral sclerosis(Wei et al.,2017;Wittung-Stafshede,2023).

Beta thalassemia syndromes:New insights

Beta thalassemia(β-thalassemia)syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin.The hallmarks of the disease include ineffective erythropoiesis,chronic hemolytic anemia,and iron overload.Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications.The management of patients with severeβ-thalassemia represents a global health problem,particularly in low-income countries.Until recently,management strategies were limited to regular transfusions and iron chelation therapy,with allogeneic hematopoietic stem cell transplantation available only for a subset of patients.Better understanding of the underlying pathophysiological mechanisms ofβ-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options,including pharmacologic enhancers of effective erythropoiesis and gene therapy.

The complexities underlying age-related macular degeneration： could amyloid beta play an important role？

e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.

经颅磁声电刺激对健康与帕金森病大鼠神经回路中beta振荡的影响

背景:经颅磁声电刺激是一种基于磁声耦合电效应的无创、高精度脑神经聚焦刺激方法,可调节神经节律振荡活动,从而影响大脑的运动、认知等功能。目的:探究经颅磁声电刺激对健康与帕金森病大鼠神经回路中beta振荡的影响。方法:①动物实验:采用随机数字表法将24只Wistar大鼠随机分为4组,每组6只:正常对照组不进行任何干预;正常刺激组大脑前额叶皮质接受经颅磁声电刺激(空间峰值脉冲平均强度为13.33 W/cm^(2),基波频率为0.4 MHz,基波周期数为1000,脉冲重复频率为200 Hz);模型对照组、模型刺激组通过腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶建立帕金森病模型,造模成功后,模型对照组大脑前额叶皮质接受经颅磁声电假刺激,模型刺激组大脑前额叶皮质接受经颅磁声电刺激,每天刺激时长2.0 min,刺激结束停留8-10 min后,采集大鼠执行T迷宫过程中局部场电位信号并同时记录行为学正确率,对比分析各组局部场电位信号能量的时频分布情况和行为差异,当大鼠正确率连续3 d高于80%后停止刺激实验和T迷宫实验。②建模仿真实验:构建经颅磁声电刺激下皮质-基底神经节回路模型,分别改变超声发射周期(5,10,20 ms)、超声发射占空比(30%,50%,90%)和感应电流密度(20,50,100μA/cm^(2)),比较不同刺激参数下健康与帕金森病大鼠beta振荡的功率谱密度值。结果与结论:①动物实验:正常对照组大鼠的空间学习能力强于模型对照组(P<0.001),正常刺激组大鼠的空间学习能力强于正常对照组(P<0.05),模型刺激组大鼠的空间学习能力强于模型对照组(P<0.01);正常对照组beta振荡能量分布较为集中,正常刺激组较正常对照组beta振荡信号能量有所降低,模型对照组与模型刺激组beta振荡能量广泛分布且能量值显著高于正常对照组、正常刺激组,并且模型刺激组beta振荡信号能量明显低于模型对照组;②建模仿真实验:不加刺激时,健康大鼠beta频段功率谱密度峰值(30 dB)显著低于帕金森病大鼠(55 dB);施加经颅磁声电刺激后,两组大鼠beta频段功率谱密度值普遍降低;beta频段功率谱密度峰值与超声发射周期呈正相关、与感应电流密度呈负相关,当超声发射占空比为50%时功率谱密度峰值最低;③结果表明:经颅磁声电刺激可抑制健康与帕金森病大鼠的beta振荡,进而改善大鼠的运动功能与决策认知功能。

Amyloid beta通过激活NLRP3炎症小体在湿性年龄相关性黄斑变性发病中的分子机制研究

目的:探讨Amyloid beta(Aβ)通过激活核苷酸结合寡聚化结构域样受体3(NLRP3)炎症小体在湿性年龄相关性黄斑变性发病中的分子机制。方法:30只C57BL/6J小鼠按数表法随机分为对照组、实验1组与实验2组,每组各10只。实验1组与实验2组进行Aβ玻璃体腔注射,注入剂量为1μL(1μmmol/L)Aβ与10μL(1μmmol/L)Aβ,对照组玻璃体腔内注射等量生理盐水。检测小鼠视网膜功能与NLRP3炎症小体表达变化情况。结果:所有小鼠在注射后7 d与14 d的视网膜各层结构清晰、细胞排列整齐,未出现炎症细胞浸润与明显的组织结构紊乱。玻璃体注射后7 d与14 d,实验1组与实验2组的视网膜a波振幅、b波振幅均低于对照组,且实验2组低于实验1组(P<0.05)。实验1组与实验2组玻璃体中的IL-6、TNF-α值与NLRP3、Caspase-1蛋白相对表达水平高于对照组,且实验2组高于实验1组(P<0.05)。玻璃体注射后7 d与14 d,实验1组与实验2组眼球中的SOD活性低于对照组,且实验2组低于实验1组(P<0.05)。结论:Aβ可通过激活NLRP3炎症小体的表达,抑制SOD活性,诱发炎症因子的释放,从而在湿性年龄相关性黄斑变性发病中发挥重要作用。

基于Beta分布的目标搜索概率自适应更新策略及其应用

针对不确定先验信息条件下的目标搜索问题,考虑传感器探测概率和虚警概率,设计了基于Beta分布的目标搜索概率自适应更新策略。首先,通过Beta分布建立了不确定先验环境的概率地图,并提出自适应目标搜索概率更新策略,使得无人机能够根据概率信息图动态更新检测次数;其次,在概率更新策略中引入了拒绝概率修正因子,根据地图概率差动态调整概率变化量,避免了搜索任务中可能存在的误检漏检问题;最后,通过数值仿真实验,验证了提出的目标搜索自适应更新策略可在不影响搜索效率的前提下,有效减小无人机的错误检测概率。

The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease

Neurovascular dysfunction,as an integral part of Alzheimer's disease,may have an important influence on the onset and progression of chronic neurodegenerative processes.The bloodbrain barrier(BBB)pathway is one of the main pathways that mediates the clearance of amyloidbeta(Aβ)in the brain parenchyma.A large number of studies have shown that receptors and ATPbinding cassette transporte rs expressed on endothelial cells play an important role in Aβtransport across the BBB,but the specific mechanism is not clear.In this review,we summarize the possible mechanisms of Aβproduction and clearance,and in particular the relationship between Aβand brain capillary endothelial cells.Aβis produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions.Dys regulation of Aβclearance is considered to be the main reason for the massive accumulation of Aβin the brain parenchyma.Several pathways mediating Aβclearance from the brain into the periphery have been identified,including the BBB pathway,the blood-cerebros pinal fluid barrier and arachnoid granule pathway,and the lymphoidrelated pathway.Brain ca pilla ry endothelial cells are the key components of Aβclearance mediated by BBB.Receptors(such as LRP1,RAGE,and FcRn)and ATP-binding cassette transporters(such as P-gp,ABCA1,and ABCC1)expressed on endothelial cells play a critical role in Aβtranscytosis across the BBB.The toxic effects of Aβcan induce dysregulation of receptor and transpo rter expression on endothelial cells.Excessive Aβexerts potent detrimental cerebrovascular effects by promoting oxidative stress,inducing chronic inflammation,and impairing endothelial structure and functions.All of these are main causes for the reduction in Aβclearance across the BBB and the accumulation of Aβin the brain parenchyma.Therefo re,studies on the intera ctions between Aβand brain capillary endothelial cells,including their receptors and transporters,studies on inhibition of the toxic effects of Aβon endothelial cells,and studies on promoting the ability of endothelial cells to mediate Aβclearance may provide new therapeutic strategies for Aβclearance in Alzheimer's disease.

Enzyme-digested Colla Corii Asini(E’jiao) prevents hydrogen peroxide-induced cell death and accelerates amyloid beta clearance in neuronal-like PC12 cells

As an aging-associated degenerative disease,Alzheimer’s disease is characterized by the deposition of amyloid beta(Aβ),oxidative stress,inflammation,dysfunction and loss of cholinergic neurons.Colla Corii Asini(CCA)is a traditional Chinese medicine which has been used for feebleness-related diseases and anti-aging.CCA might delay aging-induced degenerative changes in neurons.In the present study,we evaluated antioxidant activity,cytoprotective effects,and Aβremovability of enzyme-digested Colla Corii Asini(CCAD).Oxygen radical absorbance capacity(ORAC)activity assay showed that,as compared to gelatins from the skin of porcine,bovine and cold water fish,CCA exhibited the highest ORAC activity.The ORAC activity of CCA and CCAD was increased gradually by the length of time in storage.Ultrastructure analysis by scanning electron microscopy showed that among CCA manufactured in 2008,2013,2017 and gelatin from cold water fish skin,CCA manufactured in 2008 presented the smoothest surface structure.We further tested the protective effects of CCAD(manufactured in 2008)and enzyme-digested gelatin from cold water fish skin(FGD)on hydrogen peroxide(H2O2)-induced cell death in nerve growth factor-differentiated neuronal-like PC12 cells.Presto blue assay showed that both FGD and CCAD at 0.5 mg/m L increased cell viability in H2O2-treated neuronal-like PC12 cells.The protection of CCAD was significantly superior to that of FGD.Acetylcholinesterase(Ach E)assay showed that both FGD and CCAD inhibited Ach E activity in nerve growth factor-differentiated neuronal-like PC12 cells to 89.1%and 74.5%of that in non-treated cells,respectively.The data suggest that CCAD might be able to increase the neurotransmitter acetylcholine.Although CCAD inhibited Ach E activity in neuronal-like PC12 cells,CCAD prevented H2O2-induced abnormal deterioration of Ach E.ELISA and neprilysin activity assay results indicated that CCAD reduced amyloid beta accumulation and increased neprilysin activity in Aβ1–42-treated neuronal-like PC12 cells,suggesting that CCAD can enhance Aβclearance.Our results suggest that CCA might be useful for preventing and treating Alzheimer’s disease.

Protective effects of Dendrobium nobile Lindl. alkaloids on amyloid beta(25–35)-induced neuronal injury

Dendrobium nobile Lindl.alkaloids（DNLA）,the active ingredients of a traditional Chinese medicine Dendrobium,have been shown to have anti-oxidative effects,anti-inflammatory action,and protective effect on neurons against oxygen-glucose deprivation.However,it is not clear whether DNLA reduces amyloid-beta（Aβ）-induced neuronal injury.In this study,cortical neurons were treated with DNLA at different concentrations（0.025,0.25,and 2.5 mg/L）for 24 hours,followed by administration of Aβ（25-35）（10μM）.Aβ（25-35） treatments increased cell injury as determined by the leakage of lactate dehydrogenase,which was accompanied by chromatin condensation and mitochondrial tumefaction.The damage caused by Aβ（25-35） on these cellular properties was markedly attenuated when cells were pretreated with DNLA.Treatment with Aβ（25-35）down-regulated the expressions of postsynaptic density-95 mRNA and decreased the protein expression of synaptophysin and postsynaptic density-95,all changes were significantly reduced by pretreatment of cells with DNLA.These findings suggest that DNLA reduces the cytotoxicity induced by Aβ（25-35） in rat primary cultured neurons.The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated,at least in part,through the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95.

Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer's disease

Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei- mer＇s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer＇s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg- radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer＇s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer＇s disease treatment.

Hyperoside protects the blood-brain barrier from neurotoxicity of amyloid beta 1–42

Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo against Aβ. Our previous study found that hyperoside suppressed Aβ1-42-induced leakage of the BBB, however, the mechanism remains unclear. In this study, bEnd.3 cells were pretreated with 50, 200, or 500 μM hyperoside for 2 hours, and then exposed to Aβ1-42 for 24 hours. Cell viability was determined using 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay. Flow cytometry and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay were used to analyze cell apoptosis. Western blot assay was carried out to analyze expression levels of Bax, Bcl-2, cytochrome c, caspase-3, caspse-8, caspase-9, caspase-12, occludin, claudin-5, zonula occludens-1, matrix metalloproteinase-2（MMP-2）, and MMP-9. Exposure to Aβ1-42 alone remarkably induced bEnd.3 cell apoptosis; increased ratios of cleaved caspase-9/caspase-9, Bax/Bcl-2, cleav ed caspase-8/caspase-8, and cleaved caspase-12/caspase-12; increased expression of cytochrome c and activity of caspase-3; diminished levels of zonula occludens-1, claudin-5, and occludin; and increased levels of MMP-2 and MMP-9. However, hyperoside pretreatment reversed these changes in a dose-dependent manner. Our findings confirm that hyperoside alleviates fibrillar Aβ1-42-induced BBB disruption, thus offering a feasible therapeutic application in Alzheimer＇s disease.

SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes

Previous studies have shown that sirtuin 1（SIRT1） reduces the production of neuronal amyloid beta（Aβ） and inhibits the inflammatory response of glial cells, thereby generating a neuroprotective effect against Aβ neurotoxicity in animal models of Alzheimer＇s disease. However, the protective effect of SIRT1 on astrocytes is still under investigation. This study established a time point model for the clearance of Aβ in primary astrocytes. Results showed that 12 hours of culture was sufficient for endocytosis of oligomeric Aβ, and 36 hours sufficient for effective degradation. Immunofluorescence demonstrated that Aβ degradation in primary astrocytes relies on lysosome function. Enzymatic agonists or SIRT1 inhibitors were used to stimulate cells over a concentration gradient. Aβ was co-cultured for 36 hours in medium. Western blot assay results under different conditions revealed that SIRT1 relies on its deacetylase activity to promote intracellular Aβ degradation. The experiment further screened SIRT1 using quantitative proteomics to investigate downstream, differentially expressed proteins in the Aβ degradation pathway and selected the ones related to enzyme activity of SIRT1. Most of the differentially expressed proteins detected are close to the primary astrocyte lysosomal pathway. Immunofluorescence staining demonstrated that SIRT1 relies on its deacetylase activity to upregulate lysosome number in primary astrocytes. Taken together, these findings confirm that SIRT1 relies on its deacetylase activity to upregulate lysosome number, thereby facilitating oligomeric Aβ degradation in primary astrocytes.

Effects of natural-cerebrolysin-containing serum on neurotoxicity and synaptogenesis in amyloid-beta 1-40-induced Alzheimer's disease in vitro models

BACKGROUND： Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer＇s disease. Microtubule-associated protein 2 （MAP2） is of importance for neuronal, axonal, and dendritic generation, extension, and stabilization, as well as for the regulation of synaptic plasticity. OBJECTIVE： To investigate the antagonistic effects of natural-cerebrolysin-containing serum on beta amyloid protein 1-40 （Aβ1-40）-induced neurotoxicity from the standpoints of cell proliferation, synaptogenesis, and cytoskeleton formation （MAP2 expression）. DESIGN, TIME AND SETTING： A paralleled, controlled, neural cell, and molecular biology experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University between February 2006 and April 2008. MATERIALS： PC12 cells, derived from the rat central nervous system, were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences, China. A β1-40 was provided by Sigma, USA. Natural-cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. The natural-cerebrolysin was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yixingye （Ginkgo Leaf） in a proportion of 1：2：2. Following conventional water extraction technology, an extract （1：20） was prepared. Each gram of extract equaled 20 grams of crude drug. In a total of 12 adult male New Zealand rabbits, six underwent intragastric administration of natural-cerebrolysin extract for 1 month to prepare natural-cerebrolysin-containing serum, and the remaining six rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： An AIzheimer＇s disease in vitro model was induced in PC12 cells using Aβ1-40. The cells were incubated with varying doses of natural-cerebrolysin-containing serum （2.5%, 5%, and 10%）. Normal blank serum-treated PC12 cells served as a blank control group. MAIN OUTCOME MEASURES： Through the use of inverted phase contrast microscope, cell morphology and neurite growth were observed, neurite length was measured, and the percentage of neurite-positive cells was calculated. Cell proliferation rate was determined by MTT assay, and MAP 2 expression was detected by fluorescent immunocytochemistry. RESULTS： Following Aβ1-40 treatments, some PC12 cells were apoptotic/dying, and only a few short neurites were observed. Following interventions with natural-cerebrolysin-containing serum, the PC12 cells proliferated, there was an increased number of neurites, and neurite length was enhanced. After middle- and high-dose natural-cerebrolysin treatments, the percentage of neurite-positive cells, as well as the average length of neurites, was significantly greater than the normal blank serum-treated PC12 cells （P 〈 0.05 or P 〈 0.01）. Compared with the blank control group, MAP2 expression in the Aβ1-40-treated PC12 cells was significantly inhibited, and the cell proliferation rate was significantly decreased （P 〈 0.01）. Following incubations with natural-cerebrolysin-containing serum, MAP2 expression and cell proliferation rate in the PC12 cells were significantly increased in a dose-dependent manner, compared with treatments with blank control serum （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Natural-cerebrolysin exhibited antagonistic effects on neurotoxicity in Aβ1-40 induced Alzheimer＇s disease in vitro models. These effects were likely related to cell proliferation and the upregulation of intracellular MAP2 expression.