Tanshinone ⅡA improves Alzheimer’s disease via RNA nuclearenriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has shown potential neuroprotective effects;however,the mechanisms underlying such a function remain unclear.AIM To investigate potential Tan-ⅡA neuroprotective effects in AD and to elucidate their underlying mechanisms.METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology.To assess changes in oxidative stress and neuroinflammation,we performed enzyme-linked immunosorbent assay and western blotting.Additionally,the effect of Tan-ⅡA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Genetic changes related to the long non-coding RNA(lncRNA)nuclear-enriched abundant transcript 1(NEAT1)/microRNA(miRNA,miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.RESULTS In vivo,Tan-ⅡA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice.In vitro experiments showed that Tan-ⅡA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability,apoptosis,oxidative stress,and neuroinflammation.In this process,the lncRNA NEAT1-a potential therapeutic target-is highly expressed in AD mice and downregulated via Tan-ⅡA treatment.Mechanistically,NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p,which activates nuclear factor kappa-B(NF-κB)signaling,leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein,which exacerbates AD.Tan-ⅡA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.CONCLUSION This study demonstrates that Tan-ⅡA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway,serving as a foundation for the development of innovative approaches for AD therapy.

Early-Onset Alzheimer’s Disease and Metabolic Dysfunction, a Comparative Review

Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individuals that are diagnosed with early-onset Alzheimer’s disease. It is understood that these individuals see faster effects of the disease and die considerably sooner, but it is not understood why. This review compares the early-onset (EOAD) and late-onset (LOAD) types to try and determine some of the most blaring differences between the two. The genetic basis linking EOAD and LOAD has been the apolipoprotein E gene (APOE) to indicate metabolic alteration with the ε4 allele specifically. The topographical atrophy disparities between EOAD and LOAD supported the more noticeable cognitive differences between the two Alzheimer’s disease categories. The faster and wider spread atrophy of EOAD patients correlates with the difficulty they experience with attention, language, visuo-spatial, and executive functions. Finally, brain metabolism differs between both AD subtypes as well, where EOAD indicates the wide spread damage and metabolic breakdown across more diverse regions of the brain.

Alzheimer’s disease:a tale of two diseases?

Sporadic late-onset Alzheimer’s disease(SLOAD)and familial early-onset Alzheimer’s disease(FEOAD)associated with dominant mutations in APP,PSEN1 and PSEN2,are thought to represent a spectrum of the same disorder based on near identical behavioral and histopathological features.Hence,FEOAD transgenic mouse models have been used in past decades as a surrogate to study SLOAD pathogenic mechanisms and as the gold standard to validate drugs used in clinical trials.Unfortunately,such research has yielded little output in terms of therapeutics targeting the disease’s development and progression.In this short review,we interrogate the widely accepted view of one,dimorphic disease through the prism of the Bmi1+/–mouse model and the distinct chromatin signatures observed between SLOAD and FEOAD brains.

Presenilin mutations and their impact on neuronal differentiation in Alzheimer’s disease

The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease form.Presenilin 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and E-cadherin,LRP,Syndecan,Delta,Jagged,CD44,ErbB4,and Nectin1a.Presenilin 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and plasticity.Therefore,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease pathogenesis.This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer’s disease.Furthermore,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.

The Impact of Alzheimer’s Disease on the Life of Family Caregivers: A Phenomenological View

The objectives of this study are to describe the perception of caregivers about the process of caring for elders with Alzheimer’s disease, analyze the impact of the care process on the caregiver’s life from the biological and emotional aspects, and discuss the changes in the caregiver’s life in the light of Gestalt Therapy. This was a qualitative and descriptive study with a phenomenological analysis. The results showed that family caregivers are in a vulnerable situation because they are usually women who are also aging or are already elderly, who do not receive the necessary support to meet their needs. Because of the demands of providing care for Alzheimer’s patients, caregivers fail to consider their own issues and develop more mechanized ways of relating to their situation, using crystallization as a defense mechanism. Stress and isolation can adversely affect the physical and mental health of caregivers.

Perspectives on a collaborative Canada-China research program on diagnostic biomarkers for pre-dementia stages of Alzheimer’s disease

As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The registration networks have collected hundreds of pedigrees, for which genetic screening, neuropsycholog-ical tests and amyloid and tau imaging was used to study diagnostic biomarkers for preclinical and mild cognitive impairment （MCI） stages of AD. Besides identifying ped-igrees with novel mutations in presenilins （PSENs）/amy-loid precursor protein （APP）, the program has benefted training of Chinese research fellows, AD clinical trials forprevention,the ethical concernsfor clinical fndings, and other collaborative projects with Chinese investiga-tors. Further research of the collaborative program may facilitate the testing and clinical use of novel treatments for EOFAD and late onset AD and contribute to dementia prevention strategies in Canada and China.

Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases

The contactin-associated protein （Caspr） family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family- CNTNAP1 （Casprl）, CNTNAP2 （Caspr2）, CNTNAP3 （Caspr3）, CNTNAP4 （Caspr4） and CNTNAP5 （Caspr5）, Casprl-5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Casprl participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.

Investigation of a Chinese pedigree with early-onset familial Alzheimer’s disease caused by presenilin 1 p.M233T mutation

Objective To analyze the clinical presentation andgenotype of a Chinese pedigree with early-onset familialAlzheimer's disease. Methods A pedigree with early-onsetfamilial Alzheimer's disease was recruited. The clinicaldata of the proband who was admitted to ShengjingHospital in March 2018 and the family members werecollected. The DNA sequences of 53 dementia relatedgenes were screened using next-generation sequencingtechnology in the blood sample of the proband. The point mutation discovered in the proband was also investigatedin some family members. Results There were five memberswith Alzheimer's disease in the pedigree,includingthe proband,a 42 years old female. The onset age of apedigree member was 33 years and that of the probandwas 37 years. A point mutation from T to C at position698 (M233T) in the exon 7 of presenilin 1 (PS1) genewas found in the proband and two other family memberswho were clinically normal. Conclusion The M233T mutationof PS1 gene can lead to early-onset familialAlzheimer's disease. This family is the first pedigree withM233T mutation of PS1 gene in China,which deservesclinical attention.

Genetic profiles of familial late-onset Alzheimer’s disease in China:The Shanghai FLOAD study

Compared with early-onset familial AD(FAD),the heritability of most familial lateonset Alzheimer’s disease(FLOAD)cases still remains unclear.However,there are few reported genetic profiles of FLOAD to date.In the present study,targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population.Results show a significantly lower rate of mutation in APP and PSENs,and APOE e4 genetic risk is higher for FLOAD.Among the Chinese FLOAD population,the most frequent variant was CR1 rs116806486[5.6%,95%CI(1.8%,12.5%)],followed by coding variants of TREM2(4.4%,95%CI(1.2%,10.9%))and novel mutations of ACE[3.3%,95%CI(0.7%,9.4%)].Next,we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE e4 status.Evidence from the Alzheimer’s disease Neuroimaging Initiative(ADNI)database also supported this finding in different ethnicities.Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.

The local mammalian target of rapamycin(mTOR) modulation:a promising strategy to counteract neurodegeneration

Alzheimer’s disease (AD) and the evolution of the “Amyloid Hypothesis”: The primary risk factor for dementia is aging, as the overwhelming majority of individuals who have the disease (~95%) are 65 years old or older, and the rate of development of AD doubles roughly every five years from that age, peaking at a nearly 50% population prevalence by the age of 85. The disease is progressive and irreversible, with an average time course of 8 to 10 years. Regardless of catastrophic forecasts for the next decades, its actual prevalence has huge family and social costs.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

家庭模拟疗法在阿尔茨海默病老年病人中的应用研究

目的:研究家庭模拟疗法在阿尔茨海默病老年病人管理中的临床应用效果。方法:选取2019年1月—2022年12月医院收治的178例阿尔茨海默病(Alzhimer′s disease,AD)老年病人为研究对象,将其按照随机数字表法分为观察组与对照组,每组89例。对照组实施常规院内干预方案与延续管理方案,观察组在对照组的基础上应用家庭模拟疗法。干预结束后比较两组痴呆情况、认知功能、抑郁状况、生活质量及家庭负担情况。结果:干预后两组痴呆简易筛查量表(BSSD)及简易精神状态检查(MMES)得分均升高,且观察组高于对照组(P<0.05);干预后两组康奈尔痴呆抑郁量表(CSDD)得分均下降,AD病人生活质量量表(QOL-AD)得分均升高,且观察组改善情况优于对照组(P<0.05);干预后观察组家庭疾病负担量表(FBS)得分低于对照组(P<0.05)。结论:家庭模拟疗法能够改善阿尔茨海默病病人的痴呆情况、认知功能,抑郁状况及生活质量,减轻家庭负担程度。

阿尔茨海默病家庭照顾者连带病耻感与社会支持、一般自我效能感的关系研究

目的:调查阿尔茨海默病家庭照顾者连带病耻感、社会支持、一般自我效能感现状及相关性,探索自我效能感在连带病耻感与社会支持间的中介效应。方法:对2020年12月—2021年11月河南中医药大学3所附属医院老年病科、脑病科门诊及住院部的阿尔茨海默病病人的家庭照顾者采用一般资料调查表、连带病耻感量表(ASS)、社会支持评定量表(SSRS)、一般自我效能感量表(GSES)进行调查。结果:阿尔茨海默病家庭照顾者连带病耻感得分(56.15±7.10)分,社会支持得分(38.97±7.36)分,一般自我效能感得分(23.79±4.04)分;连带病耻感与社会支持、一般自我效能感均呈负相关(r=-0.604,P<0.01;r=-0.569,P<0.01),社会支持与一般自我效能感呈正相关(r=0.645,P<0.01);一般自我效能感在社会支持对连带病耻感的影响中发挥中介效应,中介效应占比32.79%。结论:提示临床工作者不仅可通过完善社会支持体系增强家庭照顾者的信心,还可依据一般自我效能感的中介效应,通过提升照顾者的自我效能感,间接的激发照顾者的积极感受,避免负面经历和情绪的积累内化,降低连带病耻感。

家庭尊严干预在阿尔茨海默病中的应用研究进展

对家庭尊严干预的相关概念、实施方案、实施过程、评价工具及应用效果进行综述,旨在为我国老年认知障碍病人家庭开展家庭尊严干预提供参考。

回归家庭干预对阿尔茨海默病患者认知功能和生活质量的影响

目的 探讨回归家庭干预对阿尔茨海默病患者认知功能和生活质量的影响,促进患者回归家庭。方法 将64例首次入院的老年阿尔茨海默病患者,按患者所居住社区分为对照组与观察组,每组各32例。对照组实施精神科常规护理;观察组在对照组基础上实施基于作业训练的回归家庭干预。干预前、干预后6个月比较两组认知功能、日常生活活动能力、生活质量得分。结果 两组分别有30例完成研究。干预后6个月,观察组认知功能、日常生活活动能力、生活质量评分显著高于对照组(均P<0.05)。结论 回归家庭干预能改善阿尔茨海默病患者的认知功能,提高工具性日常生活活动能力和生活质量。

老年痴呆家庭照顾者疾病不确定感与焦虑的现状研究

目的:以老年痴呆家庭照顾者为调查对象,调查其疾病不确定感、焦虑及健康问题现状。方法:采取便利抽样的方法,选取吉林省三级甲等医院老年科的老年痴呆家庭照顾者共计89例,调查其疾病确定感、焦虑及健康问题现状。结果:调查显示家庭照顾者疾病不确定感平均分是(86.79±13.72)分;焦虑调查现状中,轻度焦虑占31.45%,中度焦虑占55.06%,重度焦虑占13.49%;健康状况显示约有32.58%处于亚健康状况,约有65.17%患有高血压、心脏疾病、糖尿病等不同程度的慢性疾病。结论:针对以上调查结果,患者疾病的发展过程是影响家属疾病不确定感的重要因素,随着疾病时间的延长会增加其焦虑感。医护人员应予以重视,采取相应的护理措施,提高其生活质量。

护理干预对老年痴呆患者家属社会支持的影响

目的:探讨护理干预对老年痴呆患者家属社会支持的影响。方法:选择老年痴呆患者家属60名随机分为研究组和对照组各30名,对照组不进行干预,研究组进行持续、有效的护理干预。采用社会支持量表对老年痴呆患者家属进行测评分析,了解老年痴呆患者家属的社会支持情况。结果:干预后研究组社会支持评分显著高于对照组(P<0.05)。结论:老年痴呆患者家属的社会支持较低,加强对老年痴呆患者家属的心理指导,并提供足够的社会支持,有利于提高老年痴呆患者家属的心理健康水平,从而提高生活质量。

阿尔茨海默病病人家庭照顾者消极情绪自我应对策略研究

[目的]从照顾者角度探索阿尔茨海默病病人家庭照顾者自身消极情绪的应对方法与策略。[方法]以批判理论为哲学基础,以个案研究为理论指导,对14位积极有效应对自身消极情绪的阿尔茨海默病病人家庭照顾者进行问卷调查、半结构深度访谈及非正式交谈,资料分析采用主题分析法。[结果]阿尔茨海默病病人家庭照顾者应对消极情绪的方法与策略,包括内在应对和外在应对,内在应对促进及改善外在应对,外在应对提升内在应对,其下含有不等主题与副主题。[结论]干预者应充分发挥阿尔茨海默病病人家庭照顾者自身发展的消极情绪应对策略的作用与优势,提供应有的外界支持,使其及时有效地利用内、外在应对方法与策略,从整体上改善照顾感受,最终提高照顾者及病人的生活质量。

阿尔茨海默病患者的家庭照料者心理健康状况及其影响因素分析

目的对阿尔茨海默病（AD）患者家庭照料者的心理健康状况及相关因素进行评估。方法采用便利取样方法,选取2013年1-12月符合《国际疾病分类》（ICD-10）诊断标准的64例AD患者及其直系亲属照料者为调查对象,采用症状自评量表90（SCL-90）、Zarit照料负担量表（ZBI）、社会支持评定量表（SSRS）以及简易智力状态检查（MMSE）、日常生活功能量表（ADL）、神经精神科问卷（NPI）分别对照料者和患者进行心理测评,并对有关因素进行调查。结果 ①AD患者家庭照料者的SCL-90总分及躯体化、强迫、人际关系敏感、敌对、恐怖、偏执、精神病性因子评分均显著高于中国常模,差异有统计学意义（P〈0.05或P〈0.01）。②有躯体病、医疗费高的患者、混合型痴呆的家庭照料者SCL-90评分显著高于无躯体病、医疗费低的患者、经典型痴呆的家庭照料者,差异均有高度统计学意义（均P〈0.01）。③家庭照料者SCL-90总分与ZBI总分呈显著正相关（r=0.924,P〈0.01）,与SSRS总分呈负相关（r=-0.288,P〈0.05）,与主观支持得分呈显著负相关（r=-0.355,P〈0.01）。④主要影响因素按偏回归系数由大到小依次为ZBI总分、MMSE总分、痴呆类型、ADL总分、主观支持、躯体疾病（偏回归系数β绝对值=0.831、0.186、0.145、0.108、0.089、0.081）,决定系数R^2=0.892。结论 AD患者家庭照料者的心理健康状况较差,应加强对躯体情况差、主观支持低、患者病情较重的家庭照料者的干预,减轻照料负担,促进心理健康。

互联网对阿尔茨海默症家庭照顾者居家照护知信行的影响

目的探讨互联网对阿尔茨海默症(AD)家庭照顾者居家照护知信行的影响。方法采用方便抽样的方法,将2019年7—12月在广州某三甲医院就诊且诊断为AD的86例患者的家庭照顾者,随机分为干预组和对照组。两组家庭照顾者均接受常规护理及健康指导,干预组利用“互联网+”随访及信息咨询平台——“医患通”平台、微信公众号及小程序、微信群与居家访视等干预措施,对AD家庭照顾者进行“线上+线下”结合式延续性护理,比较两组患者的生活能力、住院次数及家属照顾者的知信行、生活质量、满意度。结果干预后1、3个月两组患者的生活能力和住院次数比较,差异均无统计学意义(P>0.05)。干预后6个月,干预组住院次数低于对照组,差异有统计学意义(P<0.05)。干预后1、3、6个月,干预组的ADKS、PAC水平均高于对照组,FCTI水平低于对照组差异有统计学意义(P<0.05)。干预后1、3、6个月,干预组生活质量和满意度高于对照组,差异有统计学意义(P<0.05)。结论利用互联网对阿尔茨海默症家庭照顾者进行干预及护理有利于提高其居家照护知信行水平、生活质量和满意度,也有利于其对患者照顾水平的提高。