Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice

Alzheimer’s disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual’s sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.     

Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

Accumulation of beta-amyloid in the brain microvessels accompanies increased hyperphosphorylated tau proteins following microsphere embolism in aged rats

To define mechanisms underlying neurovascular injury following brain embolism-induced neurodegeneration, we investigated temporal and spatial pathological changes in brain microvessels up to 12 weeks after microsphere embolism (ME) induction in aged male rats. Mild ME upregulated endothelial nitric oxide synthase (eNOS) and protein tyrosine nitration in brain microvessels. Strong beta-amyloid immunoreactivity coincident with increased eNOS immunoreactivity was observed in microvessels. Immunoblotting of purified brain microvessels revealed that beta-amyloid accumulation significantly increased 1 week after ME induction and remained elevated for 12 weeks. Importantly, beta-amyloid accumulation in brain parenchyma was also observed in areas surrounding injured microvessels at 12 weeks. Levels of Alzheimer's-related hyperphosphorylated tau proteins also concomitantly increased in neurons surrounding regions of beta-amyloid accumulation 12 weeks after ME induction, as did glycogen synthase kinase (GSK3beta) (Tyr-216) phosphorylation. Taken together, ME-induced aberrant eNOS expression and subsequent protein tyrosine nitration in microvessels preceded beta-amyloid accumulation both in microvessels and brain parenchyma, leading to hyperphosphorylation of neuronal tau proteins through GSK3beta activation.     

Accelerated Tau Aggregation,Apoptosis and Neurological Dysfunction Caused by Chronic Oral Administration of Aluminum in a Mouse Model of Tauopathies

To clarify whether long‐term oral ingestion of aluminum (Al) can increase tau aggregation in mammals, we examined the effects of oral Al administration on tau accumulation, apoptosis in the central nervous system (CNS) and motor function using tau transgenic (Tg) mice that show very slowly progressive tau accumulation. Al‐treated tau Tg mice had almost twice as many tau‐positive inclusions in the spinal cord as tau Tg mice without Al treatment at 12 months of age, a difference that reached statistical significance, and the development of pretangle‐like tau aggregates in the brain was also significantly advanced from 9 months. Al exposure did not induce any tau pathology in wild‐type (WT) mice. Apoptosis was observed in the hippocampus in Al‐treated tau Tg mice, but was virtually absent in the other experimental groups. Motor function as assessed by the tail suspension test was most severely impaired in Al‐treated tau Tg mice. Given our results, chronic oral ingestion of Al may more strongly promote tau aggregation, apoptosis and neurological dysfunction if individuals already had a pathological process causing tau aggregation. These findings may also implicate chronic Al neurotoxicity in humans, who frequently have had mild tau pathology from a young age.     

Specific Detection of Pathological Three‐repeat Tau after Pretreatment with Potassium Permanganate and Oxalic Acid in PSP/CBD Brains

Immunohistochemisty with RD3, a monoclonal antibody specific for three‐repeat (3R) tau, is sometimes hampered by diffuse neuronal staining on formalin‐fixed, paraffin‐embedded sections pretreated with formic acid and heating. Additional pretreatment with potassium permanganate followed by oxalic acid completely eliminated this diffuse RD3‐immunoreactivity (IR) in neurons. Furthermore, this additional pretreatment uniformly enhanced RD3‐IR, as well as RD4‐IR, a monoclonal antibody specific for four‐repeat (4R) tau, on pathological deposits with tau IR. This enhanced sensitivity and specificity may allow more reliable identification of 3R and 4R tau in pathological deposits, which may be variable dependent on disease and regions. Cerebral cortex and midbrain from 8 patients [5 progressive supranuclear palsy (PSP) and 3 corticobasal degeneration (CBD)] were screened for RD3‐ and RD4‐IR with this improved procedure. In addition to RD4‐positive structures found both in cerebral cortex and brainstem, RD3‐positive neurofibrillary tangles (NFTs) were also found in midbrain in 7 of these 8 cases but not in the cortex. Multi‐labeling study demonstrated that most of RD3‐negative neurons were positive for RD4. This reliable demonstration of pathological 3R tau deposits in the brainstem of PSP/CBD, so far presumably characterized by deposition of 4R tau, is useful to map tau‐positive lesions according to their biochemical composition.     

醒脑开窍针刺法对缺血性中风模型大鼠基底节14—3-3tau的影响

目的：观察醒脑开窍针刺法对缺血性中风模型大鼠基底节14—3—3tau蛋白表达水平的影响。方法：成年雄性Wister大鼠随机分为醒脑开窍组、针刺对照组、假手术组、模型组,每组分为6h、24h两个时间段;除假手术组不插入线栓之外,其余各组均采用脑膜中动脉阻塞法复制缺血性中风大鼠模型,清醒之后经行为学评分合格者,醒脑开窍组选用人中穴、内关穴,针刺对照组选用曲池穴、足三里穴各针刺1次,6h组在处死之前10min再针刺1次,24h组在12h、处死前10min时分别针刺1次;各组在规定时间取缺血侧基底节,用Western—blot对结果进行分析。结果：各组针刺前后、各个时间段之间的14—3-3tau表达水平并无显著性差异。结论：①14—3-3tau在缺血性中风中也许并不参与神经的降解过程;②14-3-3tau参与缺血性中风中的神经损伤过程,表达部位不在基底节。③在缺血性中风的6h、24h时间段的病理过程中,14—3-3tau蛋白参与此病理过程,但是表达水平很低,需要进一步的手段才能进行检测。     

脑外伤患者血清NSE、Tau、S100、MMP-9水平与脑水肿相关性的研究

[目的] 探讨脑外伤患者血清神经烯醇化酶(NSE)、Tau蛋白、S100蛋白、基质金属蛋白酶9(MMP-9)与脑水肿的相关性.[方法] 选择2013年1月至2016年11月本院收治的96例颅脑外伤患者的临床资料,将其分为观察组,选择同期招募的60名健康者作为对照组,脑外伤患者于入院时、入院后d3和d7分别行头部CT检查评估脑水肿体积.采用ELISA法检测脑外伤患者入院当日的血清NSE、Tau、S100、MMP-9蛋白水平,所有健康对照在入选后亦检测相同指标.比较两组患者的血清NSE、Tau、S100、MMP-9蛋白水平,分析观察组脑水肿体积与各血清蛋白Pearson相关性.[结果] 观察组患者入院当日血清NSE、S100、MMP-9水平均高于对照组,差异均具有统计学意义(均P<0.05).对照组血清Tau蛋白水平高于观察组,但差异无统计学意义(P>0.05).入院时观察组患者的血清NSE、Tau、S100、MMP-9水平均与入院当天CT检测的脑水肿体积呈显著正相关性(均P<0.05);入院时血清S100、MMP-9水平与入院d3的脑水肿体积亦呈显著正性相关性(均P<0.05).入院时血清S100、MMP-9水平与脑水肿进展值呈显著正相关性.[结论] 血清NSE、Tau、S100和MMP-9水平可在一定程度上反映脑外伤后脑水肿的程度,并且MMP-9、S100还可提示脑水肿的进展可能,对评估患者受伤后脑水肿的情况具有参考价值.     

tau 蛋白与阿尔茨海默病的研究进展

阿尔茨海默病(AD)的主要病理变化之一是神经元内出现以磷酸化tau 蛋白为主要成分的神经原纤维缠结。以往研究主要集中在老年斑及Aβ层面,近年来的研究表明,tau 蛋白与AD的发生发展有着密切联系,tau 蛋白异常磷酸化已成为目前的研究点。本文从蛋白激酶及磷酸酶角度对tau蛋白磷酸化与AD之间的关系进行综述。     

SH-SY5Y细胞α7尼古丁受体蛋白抑制对tau蛋白及p38 MAPK通路的影响及其与AD发病机制的关系

目的研究α7尼古丁受体(nAChR)蛋白抑制对SH-SY5Y细胞tau蛋白磷酸化水平的影响及其与p38 MAPK通路的关系,探讨α7 nAChR调节tau蛋白磷酸化的相关机制。方法用α7 nAChR阻断剂MLA阻断SH-SY5Y细胞α7 nAChR蛋白的活化及其表达,用p38 MAPK阻断剂SB203580阻断SH-SY5Y细胞p38 MAPK信号通路蛋白的活化及其表达,Western blotting方法测定tau蛋白、p-tau(S404)、p-tau(S214)、α7 nAChR、p38 MAPK及p-p38 MAPK(Thr180/Tyr182)蛋白表达水平。结果细胞经MLA处理后,p-tau(S404)和p-tau(S214)蛋白水平明显升高(P0.01),p-p38 MAPK和α7 nAChR蛋白水平明显降低(P0.01),tau蛋白和p38 MAPK蛋白水平保持不变;经SB203580处理后,SB203580及MLA共同处理后均引起p-tau(S404)、p-tau(S214)、p-p38 MAPK和α7nAChR蛋白水平显著降低(P0.01),tau蛋白和p38 MAPK蛋白水平无变化。结论α7 nAChR可通过阻断p38MAPK信号传导通路抑制tau蛋白过度磷酸化。     

Krüppel样转录因子家族在阿尔茨海默病发病机制中的作用研究进展

阿尔茨海默病(AD)是一种中枢神经系统退行性疾病,主要病理特征是脑内β淀粉样蛋白沉积形成的老年斑和tau蛋白异常磷酸化后形成的神经纤维缠结。近年研究发现,Krüppel样转录因子在AD病理生理中扮演着不可或缺的角色,这些转录因子家族成员在细胞生长、分化、增殖、迁移、凋亡、代谢和炎症反应中具有多种调节功能。最新证据表明Krüppel样转录因子参与AD的发生发展。文中详细综述了Krüppel样转录因子家族在AD发病机制中的最新作用及其相关研究进展。