神经炎症在阿尔茨海默病发病中的作用研究

阿尔茨海默病(AD)是中枢神经系统(CNS)退行性疾病,其主要病理性特征包括β-淀粉样肽(Aβ)在细胞外沉积形成的老年斑(SP),细胞内tau蛋白异常磷酸化形成的神经元纤维缠结(NFTs)[1],以及神经元丢失伴有胶质细胞增生等。其病理生理学机制复杂,关键机制目前尚未明确。在目前的AD治疗策略中,主要以胆碱酯酶抑制剂如他可林、多奈哌齐等,但因其不良反应严重,疗效有限而临床应用受限。抗Aβ、tau蛋白去磷酸     

藏药红景天提取物络塞维缓解阿尔茨海默症病变相关研究进展

<正>阿尔茨海默症(Alzheimer disease,AD)是老年性痴呆症中最常见的形式,其严重危害老年人的生理和心理健康,给许多家庭及社会造成了极大的经济和护理负担^[1]。AD患者脑部主要的病理变化是β-淀粉样蛋白(Amyloidβ-protein,Aβ)形成神经炎斑在胞外沉积以及tau蛋白磷酸化引起胞内产生神经纤维缠结(Neurofibrillary tangles,NFT)^[2]。AD的发病机制仍不明确,但在理论和临床研究中,β-淀粉样蛋白在脑内异常聚集被认为与AD的发病具有相关性^[3],该蛋白来自其前体蛋白(Amyloid precursor protein,APP),     

阿尔茨海默病中淀粉样前体蛋白翻译后修饰的研究进展

阿尔茨海默病(AD)是常见的中枢神经系统退行性疾病。β淀粉样肽(Aβ)在脑内沉积是AD特征性病理表现之一。β淀粉样前体蛋白(APP)的翻译后修饰异常是影响APP代谢导致Aβ沉积病理过程的关键。APP通过泛素化、糖基化、磷酸化、棕榈酰化和小泛素相关修饰物(SUMO)化等形式进行翻译后修饰。APP的翻译后修饰可调控APP的剪切、降解等代谢过程,但APP的翻译后修饰影响AD的具体机制仍需进一步研究。APP的翻译后修饰调控机制的深入研究将为AD药物设计提供新思路。     

山茱萸环烯醚萜苷对APP/PS1/tau小鼠脑内阿尔茨海默病样病理变化的作用机制

目的阿尔茨海默病(AD)最典型的病理变化是β-淀粉样蛋白(Aβ)在脑部沉积形成的老年斑和过度磷酸化的tau蛋白聚集导致的神经纤维原缠结(NFT),同时伴随氧化应激、神经炎症、突触损伤、神经元变性或死亡等。本研究利用APP/PS1/tau三转基因(3x Tg)模型小鼠,观察山茱萸环烯醚萜苷(CIG)对小鼠脑内多种病理变化的影响。方法 16月龄3x Tg模型小鼠每天灌胃给予CIG 100或200 mg·kg~(-1)至18月龄。采用刚果红染色法观察3x Tg小鼠海马中老年斑沉积;Western蛋白印迹法检测tau蛋白在Thr212和Thr217位点的磷酸化水平;免疫组化法观察小鼠海马中脑源性神经营养因子(BDNF)的表达和分布;实时荧光定量PCR法(q RT-PCR)检测小鼠BDNF转录水平;尼氏染色法观察小鼠海马中尼氏小体的变化。结果 18月龄模型组小鼠与对照组相比,Aβ淀粉样斑块沉积明显增加,而给予CIG 100或200 mg·kg~(-1)均能不同程度降低脑内斑块负荷。模型组小鼠tau蛋白在Thr217位点的磷酸化水平明显升高,而在Thr212位点的磷酸化水平无明显升高;CIG治疗组能明显拮抗tau蛋白在Thr217位点的过度磷酸化。模型组小鼠海马BDNF蛋白和m RNA的水平均降低,CIG能够明显恢复BDNF蛋白和m RNA表达;模型组小鼠海马内尼氏小体数量减少,染色变浅,排列散乱,CIG有增高尼氏体数量的趋势。结论 CIG能够减少Aβ在脑内的沉积和tau蛋白异常过度磷酸化,恢复BDNF在脑内的表达,并且保护神经元。     

自噬降低异常磷酸化tau蛋白所致的神经细胞毒性

目的观察雷帕霉素和饥饿诱导的自噬对表达异常磷酸化tau蛋白的神经细胞形态、tau蛋白聚集和磷酸化tau降解的影响,探讨这两种经典的诱导自噬方式抑制磷酸化tau的细胞毒性,发挥细胞保护作用的可能机制。方法体外培养小鼠神经瘤母细胞株N2a并转染tau真核表达质粒,蛋白磷酸酯酶抑制剂冈田酸(okadaic acid,OA)诱导tau蛋白异常磷酸化,雷帕霉素(rapamycin,Rapa)或Earle's平衡盐溶液(Earle's balanced salts,EBSS)诱导细胞自噬,巴佛洛霉素A1(Bafilomycin A1,Baf A1)抑制自噬,DAB染色观察表达tau细胞的形态变化;激光共聚焦显微镜观察细胞内tau聚集体;TUNEL染色和caspase-3活性检测细胞凋亡;免疫印迹(immunoblot,IB)检测磷酸化tau和细胞自噬水平。结果过表达tau的细胞胞体变圆,突起减少;OA处理后细胞突起进一步减少甚至消失,胞质出现明显tau聚集体,凋亡细胞增加,剪切型caspase-3水平上调;Rapa和EBSS处理后的细胞形态均有一定程度改善,tau聚集体明显减少,细胞凋亡减少,剪切型caspase-3表达降低;而自噬抑制剂Baf A1处理的细胞变圆,皱缩,胞质大量tau聚集体,凋亡细胞明显增加。IB结果显示Rapa明显降低高分子量的磷酸化tau,而EBSS能明显减少低分子量磷酸化tau的水平。结论 Rapa和EBSS诱导的细胞自噬均能抑制磷酸化tau蛋白的细胞毒作用,但其发挥细胞保护作用的机制不同,Rapa诱导自噬倾向于降解磷酸化tau的寡聚体,而EBSS更易于降解低分子量的磷酸化tau蛋白。     

阿尔茨海默病中钙调蛋白与PP2A和GSK-3β的关系

阿尔茨海默病(AD)是最常见的神经退行性疾病之一,其与表型水平的认知和记忆功能障碍相关。从神经病理学的角度来看,这种疾病的特征是细胞外老年斑和细胞内神经纤维缠结(NFT)的积累以及氧化应激,局部神经元功能障碍和树突过程的退化。除了上述特征之外,近几十年的研究表明,钙蛋白酶(calpain)在细胞中广泛地被激活,胰岛素信号传导的紊乱也是AD病理学中tau蛋白过度磷酸化不可分割的一部分。钙蛋白酶是保守的特异性依靠Ca2+激活的中性半胱氨酸蛋白酶,在体内有广泛的表达。自40多年前发现以来,钙蛋白酶家族的成员已经与多种病理状况相关联,其中包括神经退行性疾病。研究发现,在AD患者脑脊液中钙蛋白酶的表达和活性升高,并发现钙蛋白酶的活化是通过可溶性Aβ蛋白激活N-甲基-D-天冬氨酸受体介导的途径实现的。另有研究表明,钙蛋白酶内源抑制剂calpastatin能抑制神经细胞的凋亡,对神经细胞起到一定的保护作用。越来越多的证据表明,信号分子磷酸化状态的平衡是细胞信号调节的关键点。因此,激酶-磷酸酶磷的平衡是非常重要的。PP2A是丝氨酸/苏氨酸蛋白磷酸酶的成员,有研究表明其在神经退行性疾病中表达异常。PP2A作为脑中最重要的丝氨酸/苏氨酸蛋白磷酸酶,其表达的失调可能加速AD的发展。并且有研究已经证明在AD患者的脑中PP2A活性降低,在基因和蛋白质水平上PP2A的各种亚基(如PP2AC)表达均减少。神经元中tau蛋白有多个丝氨酸和苏氨酸的磷酸化位点,它的过度磷酸化会影响微管的结合和解离,形成神经内神经纤维缠结,从而中断微管网络。Tau蛋白过度磷酸化是AD的主要标志之一,已经有研究表明,AD患者脑中tau蛋白磷酸化比正常受试者高3到4倍。由于蛋白质的磷酸化水平取决于激酶/磷酸酶的活性,因此tau磷酸酶和激酶活性的不平衡可能在AD中发挥决定性作用。tau蛋白的磷酸酶是PP2A,它负责超过70%的tau蛋白丝氨酸/苏氨酸蛋白去磷酸化,同时,GSK-3β被认为是最重要的tau蛋白激酶。tau蛋白的过度磷酸化与PP2A和GSK-3β的功能障碍密切相关。本文就AD中钙蛋白酶与tau蛋白磷酸酶PP2A和tau蛋白激酶GSK-3β的相关文献进行综述。     

阿尔茨海默病的可能药物靶点和临床治疗研究进展

阿尔茨海默病(AD)是高发于65岁以上人群的神经退行性疾病,其病理特征是大脑中β淀粉样蛋白(Aβ)聚集形成的老年斑、过度磷酸化的tau蛋白聚集而成的神经元纤维缠结、长期炎症反应以及神经元死亡等。因此,除了衰老之外,Aβ聚集、tau过度磷酸化、慢性炎症及神经元死亡被认为是AD的主要发病假说之一。本文介绍了基于以上假说的AD治疗靶点的研究及药物研发进展。目前进展最快的药物都基于神经保护假说,全部5个小分子AD药物都是通过调节兴奋性神经递质传递通路而改善AD患者认知障碍的,但是它们的疗效非常有限。基于这一机制的新药研发也主要集中在抑制兴奋性递质受体这一方向,然而进展有限。基于tau假说的药物主要是通过抑制tau的磷酸化、异常聚集及病理扩散。然而,由于无法特异性抑制tau的磷酸化,目前进展较快的是tau疫苗。目前处于临床试验中的4个tau相关药物有2个是tau的主动免疫疫苗,均处于Ⅰ期临床中。在Aβ假说方面,药物研发思路主要集中在抑制Aβ合成/聚集、促进Aβ清除上。由于γ-分泌酶抑制剂的临床试验因严重不良反应而失败,目前的热点是β-分泌酶(BACE1)抑制剂以及Aβ疫苗。另外,通过抗炎药物抑制患者脑内的长期慢性炎症也被认为是AD治疗的可能手段之一。虽然,非甾体类抗炎药物尚无成功案例,但仍有以其他炎症因子为靶点的药物,如沙利度胺,处于临床试验中,进展良好,值得期待。总之,目前AD药物研发的主要障碍是药物缺乏临床应用指标,特异性不强,而临床试验多由于不良反应以及疗效不足等原因而失败。虽然如此,目前仍有82种AD药物处于临床阶段,其中18种进入了Ⅲ/Ⅳ期临床。同时,计算机设计靶向药物及CRISPR/Cas9等新技术的发展为AD的治疗带来了希望。     

人参皂苷Rg1对Aβ_(25-35)诱导大鼠海马神经元tau蛋白异常磷酸化的影响

目的探讨人参皂苷Rg1对Aβ2535所致大鼠海马神经tau蛋白异常磷酸化的抑制作用及其可能机制。方法应用脑立体定向技术向成年大鼠海马背侧注射凝聚态Aβ25355nmol制备AD样大鼠模型,术后分别给予腹腔内注射不同浓度的人参皂苷Rg1(625、125、25μmol·kg-1)处理,14d后处死,采用镀银染色方法观察海马组织神经元病理改变;免疫组织化学染色方法和免疫蛋白印迹技术显示大鼠脑内[pS396]tau、[pSpS199/202]tau、[pT231]tau的表达水平情况,以及总tau蛋白的水平(tau5);免疫蛋白印迹技术检测海马组织中GSK3β和磷酸化GSK3β的水平变化。结果凝聚态Aβ2535注射组神经元纤维走行紊乱,增粗、肿胀密集成宽带状,轴突深染;而人参皂苷Rg1对神经元具有明显的保护作用,脑内总tau的水平下降,[pS396]tau、[pSpS199/202]tau、[pT231]tau的表达明显低于Aβ2535注射组(P<001),以25μmol·kg-1保护作用最明显;GSK3β和磷酸化GSK3β的水平亦明显低于Aβ2535注射组,与正常和假注射组差异无显著性(P>005),以25μmol·kg-1作用最明显。结论人参皂苷Rg1对Aβ2535诱导的AD样大鼠海马神经元具有保护作用,其机制可能是通过阻断GSK3β的活性而降低磷酸化tau蛋白的表达而实现的。     

生物活性多糖在防治阿尔茨海默病中的作用

阿尔茨海默病(AD)主要表现为认知功能障碍和记忆障碍,是一种中枢神经系统退化性疾病,发病机制复杂,目前临床尚未有能彻底治愈的有效药物。AD的病理学特征主要为脑细胞外β-淀粉样蛋白(Aβ)沉积形成的老年斑(SP),脑细胞内高度磷酸化的tau蛋白形成神经元纤维缠结(NFT)。AD病因及分子机制十分复杂,至今尚不明确,其中Aβ级联假说、自由基学说和Tau蛋白异常磷酸化学说占主要地位。目前临床上治疗AD主要以西药为主,但具有毒性大、易耐药等局限性。研究发现,中药及其有效成分如多糖具有改善学习记忆能力、抗Aβ沉积、抗NO诱导的神经毒性、抗氧化应激、抗自由基损伤、抗炎症和抑制神经细胞凋亡等多方面的作用,使其可以从多靶点的角度来对AD进行防治。多糖具有广泛的生物活性,越来越多的研究证据显示,多糖对AD的防治也具有一定的积极作用。本文详细综述了微生物多糖、植物多糖和动物多糖防治AD方面的药理作用及其机制研究进展。微生物多糖:保护神经细胞和突触,AD早期海马和内嗅皮质区域会出现神经元和突触的缺失,因此保护神经细胞和突触对于AD的治疗具有重要作用。灵芝多糖高、中剂量组能明显提高AD大鼠学习记忆能力,其提高大鼠记忆能力的作用可能是通过升高AD大鼠海马内降低的突触素/突触来实现的。植物多糖:(1)清除自由基、抗氧化,在AD发生发展过程中Aβ与氧化应激关系密切,Aβ可通过多种途径产生过氧化物和自由基,从而加剧过氧化作用对神经细胞的损伤。例如肉苁蓉多糖能明显升高AD大鼠脑组织超氧化物歧化酶(SOD)活性,降低脑内丙二醛含量,使脑内的氧自由基减少,所以肉苁蓉多糖提高AD大鼠的学习记忆能力,可能是通过减少氧自由基的损伤、加速体内自由基的清除以及抑制海马神经元的凋亡来实现的。(2)改善tau蛋白过度磷酸化,tau蛋白过度磷酸化导致NFT形成的主要原因之一,也是痴呆发病的重要机制之一。例如山茱萸多糖可通过抑制p-tau(Ser422)和p-tau(Ser396)生成,改善AD大鼠学习记忆能力。(3)抑制细胞凋亡,细胞凋亡与AD的发生、发展关系密切,AD患者大脑皮质和海马区的神经元丢失与神经细胞凋亡密切相关。所以通过抑制神经细胞凋亡延缓AD的病程进展。(4)改善能量代谢,脑组织神经细胞能量代谢障碍如葡萄糖代谢降低是AD患者的一个重要病理特征,因此改善脑组织的能量代谢障碍是目前抗痴呆的一个策略。宁夏枸杞多糖可通过缓解脑内葡萄糖代谢障碍从而改善衰老状态。动物多糖:改善中枢胆碱能系统,乙酰胆碱(ACh)是脑组织内重要的神经递质,脑内细胞外液中ACh的变化与认知功能的改变具有密切关系。综上所述,多糖具有防治阿尔茨海默病的作用,在抗AD药物开发方面有良好的应用前景。     

拟人参皂苷-F11对SAMP8小鼠认知障碍的改善作用及机制

目的阿尔茨海默病(AD)是一种常见的、以认知障碍为主要症状的中枢神经系统退行性疾病。β-淀粉样蛋白(Aβ)聚集形成的淀粉样斑块(SP)和过度磷酸化的Tau蛋白引发的神经原纤维缠结(NFT)是AD临床上的主要病理特征。拟人参皂苷F11(PF11)是西洋参茎叶中分离提取的一种三萜皂苷化合物,本文通过自发快速老化(SAMP8)模型小鼠,从Aβ沉积和Tau过度磷酸化等方面,结合神经行为学、免疫组织化学和蛋白质免疫印迹等手段,进一步评价PF11对AD模型动物认知障碍的改善作用及潜在机制。方法灌胃给予6月龄雄性SAMP 8快速衰老小鼠PF11(2,8和32 mg·kg~(-1)),在给药3个月后进行行为学实验,并检测APP和β-分泌酶(BACE1)、晚期内含体Rab7和循环内含体Rab11的表达。结果灌胃给予PF11(8和32 mg·kg~(-1))3个月可以显著改善SAMP8小鼠的识别记忆和空间学习记忆障碍,显著增加SAMP8小鼠海马和皮质中突触后致密蛋白95的水平;显著降低SAMP8小鼠海马和皮质中胞浆淀粉样蛋白前体蛋白(APP)和β-分泌酶(BACE1)的水平,减少海马和皮质中APP与晚期内含体(LE)的共定位,从而降低脑内Aβ的沉积;PF11可以显著提高SAMP8小鼠海马和皮质中异常降低的亮氨酸羧甲基转移酶(LCMT-1)水平,增加甲基化蛋白磷酸酶2A(PP2A)的水平,从而减少过度磷酸化的Tau。结论 PF11能够明显改善SAMP8小鼠的认知障碍,其机制与抑制海马和皮质脑区中APP淀粉样剪切途径进而减少Aβ沉积,以及增加PP2A活力进而减少Tau蛋白的过度磷酸化相关。     

Anti-tau oligomers passive vaccination for the treatment of Alzheimer disease

The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer's disease (AD) and many neurodegenerative diseases. Despite the poor correlation between neurofirillary tangles (NFTs) and disease progression, and evidence showing, that neuronal loss in AD actually precedes NFTs formation research until recently focused on them and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. Lately, the significance and toxicity of NFTs has been challenged and new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD. Tau intermediate aggregate (tau oligomers; aggregates of an intermediate that is between monomers and NFTs in size) can cause neurodegeneration and memory impairment in the absence of Aβ. This exciting body of evidence includes results from human brain samples, transgenic mouse and cell-based studies. Despite extensive efforts to develop a safe and efficacious vaccine for AD using Aβ peptide as an immunogen in active vaccination approaches or anti Aβ antibodies for passive vaccination, success has been modest. Nonetheless, these studies have produced a wealth of fundamental knowledge that has potential to application to the development of a tau-based immunotherapy. Herein, I discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.     

Pathological changes induced by amyloid-β in Alzheimer's disease

The pathologic hallmarks of Alzheimer's disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Progressive synaptic dysfunction and loss closely correlate with cognitive deficits in AD. Based on studies of the genes responsible for familial AD and temporal patterns of pathologic changes in AD brains, the Aβ accumulation is thought to be a primary event that influences other AD pathologies in the developmental cascade of AD. However, the details of Aβ effects on the other AD pathologies remain poorly understood. In this review, we provide an overview of the effects of Aβ in AD brains, especially focusing on synaptic dysfunction and microglia. We have recently found abnormal accumulation of a key molecule for actin assembly in NFTs of AD brains, and it was revealed that the accumulation requires not only tau pathology but also an Aβ burden in a study using transgenic mouse models of AD. Synaptic integrity is morphologically maintained by the precise regulation of actin assembly. Therefore, the results suggest the possibility that Aβ may promote NFT maturation and induce synaptic dysfunction through the disturbance of actin assembly. Thus Aβ seems to be a promoting factor in brain aging. On the other hand, we have studied microglial phagocytic ability for a compensatory pathologic reaction to Aβ accumulation. Further studies on the Aβ-dependent AD pathologies may contribute to determining novel mechanisms of AD development and new therapeutic targets in AD.     

Synthesis and preliminary evaluation of 2‐arylhydroxyquinoline derivatives for tau imaging

Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of β‐amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2‐arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [¹⁸F]THK‐523. THK‐951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (K_i = 20.7 nM); thus, we radiosynthesized a ¹¹C‐labeled THK‐951 and further studied its potential as a tau PET probe. The [¹¹C]THK‐951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [¹¹C]THK‐951 for in vivo PET imaging of tau pathology in AD. Copyright © 2013 John Wiley & Sons, Ltd.     

Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: tangle formation, amyloid-β, and microglia in Alzheimer's disease

Pathological hallmarks of Alzheimer's disease (AD) include senile plaques, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaques are composed of amyloid-β (Aβ) and are surrounded by microglia, a primary immune effector cell in the central nervous system. NFTs are formed by the intraneuronal accumulation of hyperphosphorylated tau, and progressive synaptic and neuronal losses closely correlate with cognitive deficits in AD. Studies on responsible genes of familial AD and temporal patterns of pathological changes in brains of patients with Down's syndrome (Trisomy 21), who invariably develop neuropathology of AD, have suggested that Aβ accumulation is a primary event that influences other AD pathologies. Although details of the interaction between AD pathologies remain unclear, experimental evidences to discuss this issue have been accumulated. In this paper, we review and discuss recent findings that link the AD pathologies to each other. Further studies on the interaction between pathologies induced in AD brain may contribute to provide deep insight into the pathogenesis of AD and to develop novel therapeutic, prophylactic, and early diagnostic strategies for AD.     

NeuroDefend,a novel Chinese medicine,attenuates amyloid-β and tau pathology in experimental Alzheimer's disease models

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β (Aβ) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid β (Aβ) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-β/α), Aβ and 4G8 positive Aβ burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans.     

Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation

The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer’s disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (Aβ) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase Aβ generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal Aβ generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced Aβ generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (AβPP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of Aβ as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of Aβ, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of Aβ. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent.     

Icariin decreases neuro-pathogenesis and improves learning and memory functions in Tg2576 mice

Alzheimer′s disease(AD) is one of the most common neurodegenerative diseases,showing progressive memory and cognitive deficits.The predominant neuropathological features of AD are extracellular senile plaques(SP) composed by over expression of amyloid beta protein(Aβ),hyperphosphorylation of Tau protein forming the neurofibrillary tangles(NFTs) and neuronal loss in the specific brain subregions.However,the cause of dementia of AD are still not known,the neurotoxicity of over expressed Aβ coming from the proteolysis of amyloid precursor protein(APP) may play a important role.Aβ neurotoxicity has been widely reported in vitro and in vivo,including the impairment of long term potentiation(LTP),disruption of synaptic plasticity.Aβ also triggered neuron inflammation,and disturbed neurogenesis.caused neuronal oxidative damage and apoptosis,eventually resulted in memory loss At this moment,there are no effective pharmacologic interventions that could halt the progression of AD.Current pharmacotherapies,such as acetylcholinesterase inhibitors including donepezil,rivastigmine and galantamine,and a NMDA antagonist,memantine,improve symptoms but do not block the disease progression.New strategies to slow and/or reverse the pathogenesis of patients with AD are greatly needed.Traditional Chinese Medicine such as icariin may provide an unique opportunity for seeking more safe and effective therapies for AD.In this study we were examine the protective effect of icariin on Tg2576 mice,a well established animal model of AD.Our results demonstrated that chronic treatment of Tg2576 mice with icariin from age of 8 to 11 months,could improve the memory function of Tg2576 mice.In addition,icariin decreased the APP,Aβ levels,and amyloid plaque number in Tg2576 mouse brain.Finally,icariin promoted cell proliferation and differentiation into neuron in the dentate gyrus(DG) of hippocampus in aged Tg2576 mouse.Neurogenesis following icariin administration may due to the decrease of Aβ levels and phosphodiesterase type 5(PDE5),amelioration of the Aβ neurotoxicity,and increase of brain-derived neurotrophic factor(BDNF) expression in mouse brain.In summary,aged Tg2576 mice deministrated neuropathogenesis and cognitive deficits in thebrain,.Chronic treatment of icariin in Tg2576 mice significantly decreased the neuropathogenesis and improved cognitive function.Icariin stimulates neurogenesis in aged Tg2576 mice displayed further neuro-protection in aged brain.Our results provide solid evidence in support that icariin could be a potential compound for AD therapy.     

Α-mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates β-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of β-sheet-rich amyloid oligomers or fibrils which are associated with cellular toxicity in the brain. Inhibition of Aβ aggregation could be a viable therapeutic strategy for slowing and/or preventing the progress of AD. Here we reported that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, concentration-dependently attenuated the neurotoxicity induced by Aβ-(1-40) or Aβ-(1-42) oligomers (EC(50) = 3.89 nM, 4.14 nM respectively) as observed by decreased cell viability and impaired neurite outgrowth in primary rat cerebral cortical neurons. Molecular docking and dynamics simulations demonstrated that α-M could potentially bind to Aβ and stabilize α-helical conformation. α-M was found to directly dissociate Aβ-(1-40) and Aβ-(1-42) oligomers by blotting with oligomer-specific antibodies. ThioflavinT fluorescence assay and electron microscopy imaging further demonstrated that α-M blocked the fibril formation as well as disturbed the pre-formed fibrils. Taken together, our results indicate that α-M is capable to inhibit and dissociate the Aβ aggregation, which could contribute to its effect of attenuating Aβ oligomers-induced neurotoxicity. Thus, α-M could be a great potential candidate for AD treatment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that phosphorylate protein substrates involved in Alzheimer's disease (AD), such as microtubule-associated protein tau and amyloid precursor protein (APP). GSK-3β consists of two splice variants; the major short form (GSK-3β1) distributes in many organs and the minor long form (GSK-3β2), whose structural difference is the insert of only 13 amino acid residues to the C-terminal side of the catalytic site of GSK-3β1, is present in central nervous system. However, the physiological significances of the two variants are unclear. Here we examined whether the phosphorylation activities of two variants to tau and APP are different in cells. We found that GSK-3β2 has lower phosphorylation activity to tau at AD-relevant epitope (Ser396) than GSK-3β1 in cells, whereas the two variants exhibit equivalent levels of phosphorylation activities to APP. Recombinant GSK-3β2 has also lower phosphorylation activity to tau than GSK-3β1 in vitro, although the phosphorylation activities of the two variants to a synthetic peptide substrate pGS-2 are comparable. Furthermore, the deletion of the C-terminal tail (CT) of GSK-3β2 resulted in considerable reduction of tau phosphorylation activity as compared with GSK-3β1, suggesting that the lower phosphorylation activity of GSK-3β2 to tau is attributed to weak interaction with tau through its unique higher-order structure of CT constructed by the 13 amino acids insertion. Such information may provide a clue for understanding of the physiological significance of the two splice variants of GSK-3β and a new insight into the regulation of tau phosphorylation in central nervous system.     

The Wnt pathway,cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer's disease?

Beta-amyloid protein (betaAP) is thought to cause neuronal loss in Alzheimer's disease (AD). Applied to neurons in culture, betaAP induces neuronal death and hyperphosphorylation of tau protein, which forms neurofibrillary tangles (NFTs) in AD brains. Neurons also undergo rapid apoptotic death following reactivation of a mitotic cycle. However, the molecular events that determine the fate of neurons challenged with betaAP (apoptotic death, formation of NFTs and survival) are unclear. We discuss a scenario for the pathogenesis of AD. This links betaAP-induced changes to the Wnt signaling pathway that promotes proliferation of progenitor cells and directs cells into a neuronal phenotype during brain development. We propose that betaAP-mediated facilitation of mitogenic Wnt signaling activates unscheduled mitosis in differentiated neurons. Furthermore, late downregulation of Wnt signaling by betaAP might lead to NFT formation. We propose that drugs that both inhibit the cell cycle and rescue Wnt activity could provide novel AD therapeutics.