Donepezil and galanin interactions in an animal model of Alzheimer’s disease

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AD小鼠模型介绍

AD小鼠模型介绍AD小鼠模型，即阿尔茨海默病小鼠模型，是一种用于研究阿尔茨海默病（Alzheimer's Disease, AD）的动物模型。

阿尔茨海默病是一种常见的神经退行性疾病，主要表现为认知功能障碍和记忆力丧失。

目前还没有有效的治疗方法，因此研究AD的机制和治疗方法变得至关重要。

AD小鼠模型是研究该疾病的重要工具之一AD小鼠模型通常通过基因工程技术构建，根据不同的基因突变或操纵来模拟AD发病机制和临床表现。

这些小鼠通常表现出与人类AD患者相似的一些病理特征，如神经元损伤、β淀粉样蛋白沉积、tau蛋白磷酸化等。

通过对这些AD小鼠模型的研究，科学家可以更好地了解AD的发病机制，寻找新的治疗方法和药物靶点。

目前，AD小鼠模型已经被广泛应用于AD病理生理学研究、新药筛选和临床药物评估等领域。

下面将介绍一些常见的AD小鼠模型及其特点：1. APP/PS1双转基因小鼠：这是最常见的AD小鼠模型之一，它通过表达人类APP（β淀粉样前体蛋白）和PS1（presenilin-1）基因，模拟AD的β淀粉样蛋白沉积和神经元损伤等特征。

这种模型通常表现出记忆力损失、神经退化等AD病理生理学特征。

2. 3xTg-AD小鼠：这是一种同时表达人类APP、PS1和tau蛋白P301L基因的三转基因小鼠。

该模型不仅模拟了β淀粉样蛋白和tau蛋白在AD发病中的作用，还表现出早期记忆障碍和晚期神经元损伤等表型。

3.Tg2576小鼠：这是一种表达人类APP基因的转基因小鼠模型。

该模型主要用于研究β淀粉样蛋白在AD发病中的作用，通常表现出大量的β淀粉样蛋白沉积和神经元损伤等特征。

4. 5xFAD小鼠：这是一种表达人类APP、PS1和tau蛋白基因的五转基因小鼠模型。

该模型不仅模拟了β淀粉样蛋白和tau蛋白在AD发病中的作用，还表现出更加严重的神经元损伤和认知功能障碍等表型。

除了以上几种常见的AD小鼠模型外，还有许多其他基因操纵小鼠模型被用于AD的研究。

髓样细胞触发受体2在阿尔茨海默病发病中的作用

髓样细胞触发受体2在阿尔茨海默病发病中的作用陈建玲; 李婷【期刊名称】《《医学综述》》【年(卷),期】2019(025)015【总页数】5页(P2988-2992)【关键词】阿尔茨海默病; 髓样细胞触发受体2; β淀粉样蛋白; 老年斑; tau蛋白【作者】陈建玲; 李婷【作者单位】上海交通大学医学院附属精神卫生中心老年二科上海200030; 长宁区精神卫生中心老年科上海200335【正文语种】中文【中图分类】R749.1阿尔茨海默病(Alzheimer′s disease，AD)是一种中枢神经系统退行性疾病，是老年痴呆最常见的表现形式，以细胞外β淀粉样蛋白(β amyloid protein，Aβ)沉积形成的淀粉样斑块、细胞内过度磷酸化tau蛋白形成的纤维缠结及神经炎症为主要特征性病理表现。

目前，AD的发病机制尚不完全清楚，无有效的治疗方法。

近年来，随着全基因组测序及遗传学研究方法的发展，人们发现髓样细胞触发受体2(triggering receptor expresses on myeloid cells-2，TREM2)的罕见变异可以使AD的发病风险增加[1]。

TREM2在AD病理机制中发挥作用，但其对AD发病的具体影响尚不清楚。

现对TREM2的生物学特性和作用机制及其在AD发病中的潜在作用予以综述，用来评估TREM2作为新的治疗靶点和预后/诊断生物标志物的可能性。

1 TREM2及其功能效应TREM2广泛分布于脑、肺、膀胱、肾上腺、胎盘等组织，在髓系细胞来源的树突状细胞和巨噬细胞(如小胶质细胞、破骨细胞和肺泡巨噬细胞等)中较为常见。

TREM2由1个V型免疫球蛋白样胞外结构域、含有3个赖氨酸残基的跨膜结构域和缺乏信号结构的胞质结构域构成。

TREM2的赖氨酸残基与DNAX相关蛋白12的酪氨酸残基在脂质膜上通过静电相互作用。

人类TREM2基因编码一种膜蛋白，其功能效应目前尚无定论，大多认为该膜蛋白可与DNAX相关蛋白12形成受体信号复合物，并可在免疫反应和慢性炎症中刺激结构性炎症细胞因子的产生[2]。

基于网络药理学和分子对接法的益智清心方治疗阿尔茨海默病作用机制探索

·基础研究·基于网络药理学和分子对接法的益智清心方治疗阿尔茨海默病作用机制探索△刘佳妮1，2，刘剑刚1，3，韦云1，3*，罗增刚3，4*，李浩1，31.中国中医科学院西苑医院，北京100091；2.中国中医科学院研究生院，北京100700；3.中国中医科学院西苑医院老年病研究所，北京100091；4.北京市中医药管理局，北京100053［摘要］目的：运用网络药理学及分子对接方法探讨益智清心方（YZQXF）对阿尔茨海默病（Alzheimer′s disease，AD）的作用靶点，构建活性成分-靶点-通路网络并分析其作用信号通路，探讨其对AD的防治作用及可能的分子机制。

方法：根据YZQXF药味组成，在中药系统药理学数据库与分析平台（TCMSP）检索各药材的有效化学成分及各成分相应的作用靶点；利用GeneCard、OMIM、PharmGKB、TTD、DrugBank数据库搜索AD相关靶点，同时将药物靶点及疾病靶点数据进行比对，获得交集靶点，上传STRING11.5数据库对其进行蛋白质-蛋白质相互作用（PPI）网络分析并找到核心靶点；通过Cytoscape3.7.1构建YZQXF治疗AD的活性成分-作用靶点-通路网络；借助BioConductor软件的R语言包对作用靶点进行基因本体（GO）注释和京都基因与基因组百科全书（KEGG）通路富集分析；最后将核心基因分别与关键靶标进行分子对接，验证YZQXF关键成分与核心靶点的作用特征。

结果：YZQXF中共有43个化学成分作用于2871个AD相关靶点，共存在129个化学成分-靶点相互作用关系。

YZQXF治疗AD的关键成分包括槲皮素、山柰酚、β-谷甾醇、四氢小檗碱、豆甾醇、原阿片碱、杨梅酮、氧代小檗碱、巴马汀、马卡因、小檗碱，核心靶点为丝裂原活化蛋白激酶1（MAPK1）、Myc、Fos、MAPK14、Jun、核转录因子-κB p65（RELA）、蛋白激酶B1（Akt1）、MAPK8、白细胞介素-1β（IL-1B）、肿瘤蛋白p53（TP53）。

Ivan_de_Araujo_团队揭示GLP-1_如何通过肠脑轴神经环路调控机体行为和生理学效应

第 44卷第4期2023 年 7月Vol.44 No.4July 2023中山大学学报（医学科学版）JOURNAL OF SUN YAT⁃SEN UNIVERSITY （MEDICAL SCIENCES ）Ivan de Araujo 团队揭示GLP-1如何通过肠脑轴神经环路调控机体行为和生理学效应张通（广州市第一人民医院//广州消化疾病中心//华南理工大学附属第二医院普外科广东广州 510180）作者简介：张通，广州市第一人民医院、广州消化疾病中心、华南理工大学附属第二医院，结直肠外科副主任医师，美国西奈山医学院访问学者。

现任广东省医学会胃肠外科分会青年委员，广东省精准医学会结直肠癌分会委员，广东省保健协会肛肠保健分会委员，广州市医师协会普外科分会委员。

近年来，本人主要致力于消化病学和神经科学领域的交叉研究，研究成果多次发表于Cell ，Cancer letters ，Molecular Cancer 等期刊。

主持参与多项国家自然科学基金、省自然科学基金项目，2021年参与的《结直肠癌早期筛查方案和干预的技术创新》项目荣获“广东医学科技一等奖”。

E-mail ：********************.cn 。

摘要：近期来自西奈山医学院IvandeAraujo 课题组报道了小肠分泌的内生型胰高血糖素样肽1（GLP-1）通过交感神经通路控制食欲的器官间神经环路，该工作证实了远端回肠L 细胞内分泌的GLP-1是由位于肌层的表达GLP-1R （胰高血糖素-1受体）的神经元监测，并通过腹腔交感神经节，进而介导胃动力减低和扩张。

该文进一步深入研究并发现，位于脊髓的背根神经元，是感受胃扩张，并将感觉信息传导至延髓，从而引发下丘脑与脑干协同的降低摄食行为。

这项研究为治疗腹胀，食欲减退等胃动力障碍的相关疾病提供了新的策略。

关键词：胰高血糖样肽-1；厌食；肠-脑轴中图分类号：R338.5 文献标志码：A 文章编号：1672-3554（2023）04-0718-03DOI ：10.13471/ki.j.sun.yat-sen.univ （med.sci ）.2023.0424A New Study From Ivan de Araujo Lab Reported GLP-1 Mediated Gut-Brain Neural Circuit Controls Appetite SuppressionZHANG Tong（Guangzhou First People ’s Hospital//Guangzhou Digestive Disease Center//Department of General Surgery ， The SecondAffiliated Hospital of South China University of Technology ， Guangzhou 510180， China ）Correspondence to ： ZHANG Tong ； E-mail ：********************.cnAbstract ：A new study in Cell from Ivan de Araujo and colleagues reported that intestinal GLP-1 acts on an inter-or⁃gan sympathetic neural circuit that induces appetite suppression. This study revealed that GLP-1， secreted by ileal L cells ， sensing by intestinal myenteric layer intestinofugal neurons activated a sympatho-gastro-spinal-reticular-hypotha⁃lamic pathway involved in appetite suppression ， linking stomach distention to craniofacial programs for food rejection. These molecularly indentified ， delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.Key words ： glucagon-like peptide-1； anorexia ； gut-brain axis［J SUN Yat⁃sen Univ （Med Sci ），2023，44（4）：718-720］· 专家述评·收稿日期：2022-12-13基金项目：国家自然科学基金（82173236）；西藏自治区自然科学基金【XZ2022ZR-ZY45（Z ）】第4期张通. Ivan de Araujo团队揭示GLP-1如何通过肠脑轴神经环路调控机体行为和生理学效应Ivan de Araujo课题组先前的研究报道揭示了营养物质被近端十二指肠识别后刺激其分泌CCK （cholecystokinin），诱发摄食增加并引起大脑产生愉悦奖赏的神经环路机制［1］，而同样的营养物质被传送至远端回肠则会引起厌食反射，导致摄食抑制的发生［2］。

医学英语阅读：最新发现!阿尔兹海默症(老年痴呆症)能彻底治愈吗

美联英语提供：医学英语：阿尔兹海默症（老年痴呆症）能治愈吗小编给你一个美联英语官方试听课申请链接：/?tid=16-73374-0 P．Murali Doraiswamy discusses recent breakthroughs in diagnosing Alzheimer’s disease and what everyone can do to postpone the onset of memory loss．P．Murali Doraiswamy is the head of biological psychiatry at Duke University and is a Senior Fellow at Duke’s Center for the Study of Aging．He’s also the co-author of The Alzheimer’s Action Plan，a guide for patients and family members struggling with the disease．Mind Matters editor Jonah Lehrer chats with Doraiswamy about recent advances in Alzheimer’s research and what people can do to prevent memory loss．LEHRER：What do you think are the biggest public misconceptions of Alzheimer’s disease?DORAISWAMY：The two biggest misconceptions are “It’s just aging”and “It’s untreatable，so we should just leave the person alone．”Both of these misconceptions are remnants of an outdated view that hinders families from getting the best diagnosis and best care．They were also one of the main reasons I wanted to write this book．Although old age is the single biggest risk for dementia，Alzheimer’s is not a normal part of aging．Just ask any family member who has cared for a loved one with Alzheimer’s and they will tell you how different the disease is from normal aging．Alzheimer’s can strike people as young as their forties；there are some half a million individuals in the United States with early－onset dementia．Recent research has pinpointed disruptions in specific memory networks in Alzheimer’s patients，such as those involving the posteromedial cortex and medial temporal lobe，that appear distinct from normal aging．The larger point is that while Alzheimer’s is still incurable it’s not untreatable．There are four FDA－approved medications available for treating Alzheimer symptoms and many others in clinical trials．Strategies to enhance general brain and mental wellbeing can also help people with Alzheimer’s．That’s why early detection is so important．LEHRER：Given the rapid aging of the American population －by 2050，the Alzheimer’s Association estimates there will be a million new cases annually －what are the some preventative steps that people can take to prevent or delay the onset of the disease?DORAISWAMY：Unfortunately，there isn’t yet a magic bullet forprevention．You can pop the most expensive anti－aging pills，drink the best red wine，and play all the brain games that money can buy，and you still might get Alzheimer’s．While higher education is clearly protective，even Nobel Laureates have been diagnosed with the disease，although it’s likely their education helped them stave off the symptoms for a little bit．My approach is more pragmatic －it’s about recognizing risks and designing your own brain health action plan．The core of our program is to teach people about the growing links between cardiovascular markers （blood pressure，blood sugar，body weight and BMI，blood cholesterol，C－reactive protein）and brain health．A population study from Finland has developed a fascinating scale that can predict 20－year risk for dementia –sort of a brain aging speedometer．Obesity，smoking，lack of physical activity，high blood pressure，and high cholesterol are some of the culprits this study identified．So keeping these under control is crucial．Depression is another risk factor for memory loss，so managing stress and staying socially connected is also important．B vitamins may prevent dementia in those who are deficient and there are some simple blood tests that can detect this．For the vast majority of people，however，there are no prescription medications that have been proven to prevent dementia．This means that a brain －healthy lifestyle is really our best bet for delaying the onset of memory loss．In the near future we will likely have prevention plans that are personalized based on genetic，metabolic and neurological information．In familial Alzheimer’s disease，pre-implantation genetic diagnosis has already been used to successfully deliver babies free of a deadly Alzheimer causing mutation—though only time will tell if deleting such dementia risk genes in humans has other consequences．LEHRER：Your book talks about a new technique that allows doctors to image amyloid plaques in the brain．How will these change the diagnosis of the disease?DORAISWAMY：Amyloid PET scans are in the late stages of validation testing to see if they can improve the accuracy of clinical diagnosis．The Alzheimer’s brain is defined by beta－amyloid plaques and tangles but，at present，these can only be definitively diagnosed with an autopsy．If an amyloid PET scan is “plaque negative”that will tell a doctor that Alzheimer’s is unlikely to be the diagnosis and help reassure the family．Early findings suggest that people who carry risk genes are more likely to have plaque positive scans even before they develop symptoms －suggesting that the scans could possibly be useful for predicting future risk．If true，this might eventually lead to a change in diagnostic terminology where “preclinical”Alzheimer’s is diagnosed purely based on biomarker and scan findings long before memory symptoms start．Therapies to treat Alzheimer’s by blocking amyloid plaques are already in trials but are currently given blindly topatients without knowing their brain plaque status—raising their risk for side effects and treatment failure．So this scan may also help drug development by helping select the most appropriate subjects for treatment and then monitoring treatment effects．Amyloid accumulation with aging is seen in many animal species and the scan offers us a tool to study what role plaque plays in normal brain aging．So this could do for the brain what colonoscopy did for the gut！LEHRER：Will science ever find a cure for Alzheimer’s?DORAISWAMY：It’s an incredibly tough puzzle to crack but the pace of research is so great that new drug targets are being reported daily．I think a form of cure is more likely to come from delaying the onset rather than by growing new brain cells to repair lost tissue．Realistically speaking there are several fundamental questions we don’t fully understand and have yet to answer：What causes the disease? Why do plaques and tangles form? Why are the memory centers the first to be destroyed? On the positive side，there are several dozen drugs in clinical trials．LEHRER：What recent scientific advances in treating or understanding Alzheimer’s are you most excited about?DORAISWAMY：I’m most excited about diagnostic advances．By using acombination of biomarkers，genetic tests and new brain scans，we are inching very close to predicting not only who will develop Alzheimer’s but the exact age when they may start developing symptoms．This offers huge opportunities for conducting prevention trials．Of course，it also brings a whole host of ethical challenges，since our diagnostic and predictive abilities are advancing far faster than our ability to prevent Alzheimer’s．On the treatment side，there are several developments that I am excited about．The interactions between vascular disease and memory loss suggest that at least some aspects of Alzheimer’s may be modifiable through diet and exercise．Dimebon，a drug that improves mitochondrial function，has yielded promising results and is in final stages of testing．In addition，therapeutic strategies which target the brain’s own ability to repair itself –for example，by delivering nerve growth factor through viral vectors –are in clinical trials．Until we have a cure，however，it’s really important to focus on improving the quality of life of people with Alzheimer’s．P．Murali Doraiswamy 讨论了最近阿尔兹海默症诊断方面的进展，以及人们可以做些什么以延迟记忆衰退的发生。

[科普]健忘与阿兹海默症（英文）

[科普]健忘与阿兹海默症（英⽂）其实是我⼀篇病理学作业，那教授着实与众不同，要求⽤通俗易懂的⽂字来写科学review，结果就写成了⼀篇科普⽂，左右写了，故贴上来，有兴趣看的就当增长见闻吧：）（哪天⼼情好再翻译成中⽂XD）Why People Become so Forgetful Once They Get Alzheimer's Disease?Have you ever heard about a disease called Alzheimer's? I bet most ofyou probably have heard of it from somewhere, even though you mightnot know exactly what it is. For many people who are out of thescience world, "Alzheimer's" means the same thing as "seniledementia", which is actually incorrect if you speak scientifically.More interestingly, "dementia" itself has two different meanings inthe clinical realm and the lay public. "Demented" is generally used bythe lay public synonymously with "mad" or "insane". In clinical termhowever, dementia refers to a specific and pronounced decline ofcognitive function in humans - a decline in mentation. (In Latin,dementia means "apart from mind".) "Senile dementia", often shortenedas simply "dementia", refers to the progressive cognitive declinefound in elderly people beyond what might be expected from normalaging, which is usually due to damage or disease in the brain. Inspecific, dementia can arise from a number of causes such as stroke,vascular problems, some medical conditions, or the abuse of drugs oralcohol. But among them, a pathological condition called Alzheimer’sdisease (AD) is the most common cause of senile dementia. Because ofthis, it becomes that the two terms, AD and dementia, are often usedinterchangeably in public content. However, please keep in mind thatthere are other causes that can lead to dementia besides AD.In 1906, a German psychiatrist Alois Alzheimer first described thedisease that eventually bears his name. He wrote of a 51-year-oldwoman named Mrs. Auguste D who had "a strange disease of the cerebralcortex" that manifested as progressive memory impairment and otherbehavioral and cognitive problems. After Mrs. Auguste D. died in 1906,Dr. Alzheimer carefully examined her brain anatomy and neuropathology.He presented Mrs. Auguste D's case to the German psychiatristcommunity and described the neurofibrillary tangles and amyloidplaques that were found in Mrs. Auguste D’s brain (Alzheimer,1907). “Tangles” and “plaques” have then come to be considered as thetwo main pathological hallmarks of the disease.Simply speaking, the plaques are admixtures of a bunch of junks thatbrain produces. They are found in the extracellular spaces, i.e. theoutside of the brain cells. A typical senile plaque usually containslots of aggregated proteins called amyloid beta (Ab). Scientists haveno idea why our brain produces such protein since it appears to haveno function roles. As this junk protein aggregating into a toxic densecore, the nearby dendrites and axons (the extensions of neurons) areaffected and start dying. In contrast to extracellular plaques, thesecond pathological hallmark of AD is localized intracellulary, i.e.inside of the cells. Many people may have an impression that a cell islike a small squishy water balloon (at least I used to think so),which of course is not true. The cell actually has its own skeletonstructure inside that supports its external shape. It is calledmicrotubule cytoskeleton. In AD, these microtubules and mircofibrilsbecome tangling up with each other for some reason. And eventually thetangles cause the collapse of the cytoskeleton, which leads to thecell death. Remember how your kitten can make a ball of wool into afearful tangle? Same thing can happen in our brain, but we haven’t yetfound that "naughty kitten" which causes the neurofibrillary tangles.Please don't think tangles and plaques are unique in Alzheimer's. Yourbrain is also producing plaques as you reading this line. Tangles andplaques can be found in many normal non-demented elderly, but ratherin a very reduced number and would not cause severe neuronal loss anddramatic cognitive problems. One major task for AD researchers is tofind out why the plaque and tangle forming processes are much moreaccelerated and pronounced in AD.Now you are probably wondering how these pathological alterations atthe cell level can lead to the behavioral and cognitive changes in AD patients. Among the symptoms of dementia caused by AD are losses of learning and memory capacity, decline in reasoning ability, attention problems, language difficulties and problems with perception. Forgetfulness is the most typical presenting symptom showed by AD patients in the beginning stage. These patients can remember how to talk, and may remember events from many years ago, but they have trouble remembering what happened in the past hours. Episodic memory formation is lost as the patients typically lost the recollection oftheir ongoing experiences on a daily basis. Common examples of memory deficits in this stage are the repetition of questions or statementsand the misplacement of items. The patients at this early stage of ADare unable to recall recent conversations or events, whereas the pastlife experience and knowledge learned years ago are still retrievable, clearly showing the impairment in new information acquisition but notin the retention of old memory.These early symptoms of AD remind the scientists of the cognitive changes manifested by another group of patients who lost their hippocampus. Hippocampus (meaning “seahorse” in Greek) is a structure located in the medial temporal lobe of our brain. It got its name fromits curved shape in coronal sections of the brain, which muchresembles a seahorse. Today, the hippocampus is generally believed to play a crucial role in the formation of new declarative memories about experienced events. A fancy scientific term of this process iscalled “memory consolidation”. In brief, the hippocampus serves as a short-term memory store that eventually uploads memory to the neocortex for longer-term storage. I know many people like to draw an analogy between human brain and computer (indeed, in Chinese language, the word “computer” literally means “electronic brain”). If you lookthe brain as a super powerful computer, the hippocampus will be itsRAM (random access memory) which temporarily stores information and later uploads them to the hard disk, i.e. the neocortex, for permanent storage. What if the function of the hippocampus is disrupted? Let’slook at the famous case of a patient named H.M. H.M. is an unfortunate victim of neurosurgical experimentation who had his medial temporal lobes removed as a treatment for epilepsy, the removed parts including most of his hippocami on both sides of his brain. The lesion partially treated the epilepsy but essentially completely destroyed H.M.’scapacity of forming long-term memory. He became unable to form any new long-lasting declarative memories (anterograde amnesia) and has been living a minute-to-minute existence for the past five decades ofyears. However, his prior memories are mostly intact for his lifetimeup to several years before the surgery and he is able to consistentlyrecall them (Scoville & Milner, 2000).Surprisingly, most AD patients in the initial stages have shown thesame memory problems experienced by H.M. You then might be thinking, oh, maybe there’s something wrong with their hippocampus! And that’s exactly what the scientists have found out. Early in the course of AD, plaques and tangles are found particularly abundant in a brain region called “entorhinal cortex” which sits right next to the hippocampus.This region is like a gateway to the hippocampus, and all the information going into or going out from the hippocampus have to pass through it. Without the input from the entorhinal cortex, the hippocampus cannot function properly. Very soon, the hippocampusitself gets occupied by the plaques and tangles, thus loses itsability to establish or consolidate memory for ongoing events. As the disease progresses, the plaques and tangles also start to spread outto other brain structures, meanwhile the initially affected areas are worsening. In brief, the circuitry that is critical for normaldeclarative memory, i.e. the hippocampus and its adjacent regionappear to be the first target affected by AD neuropathology such as plaques and tangles. That is why people start to become so forgetfulonce they get Alzheimer's disease.The sadness is that the “forgetfulness” is only a start for ADpatients. As the plaques and tangles start to spread out to otherlimbic regions and cerebral cortices, patients in the middle stagehave even more profound anterograde memory loss and also start to show retrograde amnesia. That is, recalling remote memories of long pastlife experience and events becomes difficult now. Recognition of knownindividuals progressively declines and verbal communication becomes incoherent. In many cases, AD patients also display mood disorders such as severe depression, since these victims are aware that they are deteriorating mentally and are “losing” loved ones. Eventually in the final stages of AD, during when the whole neocortex as well as other brain structures are profoundly affected by tangles and plaques, the patients become unable to execute the most basic cognitive functions, thus are unable to take care of themselves. They are completely bedridden until death.In these days, AD affects up to half million of people in Canada (Canadian Study of Health and Aging Working Group, 2000), 4 million in US, and 12 million worldwide over the age of 65. It is estimated thatby the year 2025 the number will go up to 20 million worldwide given the fact that at present there is no effective treatment for this disease. These dry statistical numbers probably don’t mean much to you at first glance. Let's look at it in this way then. Right now, aboutone in ten people over the age of 65 in North America have AD. If you live to age 85, you have about a one in two chance of developing this tragically debilitating disease. To me these statistics are sobering, especially given that we don’t have any effective treatment for AD. Since last century, human longevity has been greatly increased worldwide due to our expanding knowledge in biology and great improvement of health care and public hygiene. In the 18th century,the average human lifespan was around 30 years. But in the year 2005, the average life expectancy in Canada was estimated to be 80.1 years. Some scientists predicted that the USA would have 5.3 million people aged over 100 in 2100. Yes, thanks to the great Science. Nowadays we human are able to treat lots of disease and actively change our living environment to accomplish our longevity dream. But, today’s scientific advances are only able to make our bodies live longer, not our brains. It appears that our brain has a shorter “lifespan” than our bodies.Our brain starts to gradually degenerate irreversibly as early as inour 20's. In addition to the “normal aging”, we are facing more aggressive neurodegenerative conditions such as Alzheimer's that we haven't yet found a weapon to fight against. Does it make sense to become a centenarian while losing the ability to recognize your loved ones and losing all the precious memory from your past life? I don't know yours but my answer is a big NO. We need a healthy and functioning brain to make our longevity meaningful. While scientists worldwide are working so hard to seek treatments for Alzheimer’s and other brain diseases, please remember that your brain, just like therest of your body, need to be looked after. It is your own responsibility to take care of your own precious brain.K.FanReference:Alzheimer A. (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin. 64:146-48.Canadian Study of Health and Aging Working Group: Canadian Study of Health and Aging Working Group. (2000) The Incidence of Dementia in Canada. Neurology. 55: 66-73.Scoville WB, Milner B. (2000) Loss of recent memory after bilateral hippocampal lesions. 1957. J. Neuropsyychiatry Clin. Neuroscie. 12:103-13.。

老年性痴呆的细胞模型

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通过将干细胞定向分化为神经元或胶质细胞，可以构建更接近体内环境的细胞模型，用于研究老年性痴呆的发病机制和药物筛选。
干细胞模型还有助于探索老年性痴呆的基因和环境因素相互作用，以及遗传和表观遗传学在疾病发展中的作用。
干细胞模型
03
细胞模型在老年性痴呆研究中的应用
通过建立老年性痴呆细胞模型，可以筛选出具有潜在治疗作用的候选药物，为后续临床试验提供依据。
利用细胞模型研究药物的疗效和作用机制，有助于开发出更有效的治疗老年性痴呆的药物。
药物筛选与开发
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研究老年性痴呆细胞模型中细胞凋亡的机制，有助于深入了解疾病的发生和发展过程。
氧化应激
通过检测细胞模型中氧化应激相关指标，探究氧化应激在老年性痴呆中的作用。

阿尔兹海默症的神经炎症假说及其治疗潜力

阿尔兹海默症的神经炎症假说及其治疗潜力近年来，阿尔兹海默症（Alzheimer's disease）一直是备受关注的神经退行性疾病。

据统计，全球有超过5000万人患有这种疾病，而且这个数字还在不断增长。

针对阿尔兹海默症的治疗和预防一直是科学家们的关注焦点之一。

在广泛的研究中，神经炎症假说被提出并引起了人们的兴趣。

本文将探讨阿尔兹海默症的神经炎症假说及其治疗潜力。

I. 阿尔兹海默症概述阿尔兹海默症是一种神经系统退行性疾病，主要影响老年人。

其主要特征是记忆力丧失、认知功能下降和行为异常。

目前，阿尔兹海默症的具体病因尚未完全理解，但有很多因素被认为可能导致这种疾病的发生，包括遗传因素、环境因素和神经炎症。

II. 神经炎症假说神经炎症假说认为，在阿尔兹海默症中，神经系统的慢性炎症可能起到了重要的作用。

这种炎症可能由异常的免疫反应和细胞因子释放引起。

过度激活的免疫系统可能破坏神经细胞，并在大脑中形成炎症反应。

这种炎症反应会导致神经元失去功能，形成阿尔兹海默症的病理特征。

III. 神经炎症假说的证据神经炎症假说的证据主要来自临床和实验室研究。

临床研究发现，阿尔兹海默症患者的大脑中存在大量的炎症标志物，如细胞因子和炎性介质。

这些标志物的水平与疾病的严重程度呈正相关。

实验室研究则进一步证实了神经炎症与阿尔兹海默症的关联，通过使用动物模型和细胞培养实验揭示了神经炎症对神经退化的影响。

IV. 神经炎症治疗的潜力基于神经炎症假说，研究人员开始探索以抑制神经炎症为目标的阿尔兹海默症治疗策略。

一些非甾体类抗炎药物被认为可能具有防治潜力。

例如，美洛昔康和布洛芬等药物已显示出降低炎症水平的能力，并在动物模型中显示出改善认知功能的作用。

此外，一些新的药物和治疗方法正在开发中，旨在针对神经炎症路径发挥作用。

V. 多因素治疗策略的重要性尽管神经炎症治疗具有潜力，但研究人员也认识到阿尔兹海默症是一个复杂的疾病，多种因素可能同时参与。

TMEM106B_基因多态性与阿尔茨海默病发病的关系及其机制

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一种阿尔茨海默病动物模型,构建方法及应用

一种阿尔茨海默病动物模型,构建方法及应用阿尔茨海默病（Alzheimer's disease, AD）是一种神经退行性疾病，其主要病理特征为神经元丧失和神经纤维缩短。

该疾病的发病机制至今尚未完全揭示，但已经有了一些关于其病理生理学方面的研究成果。

为了更好地研究AD疾病的发生过程、病理变化以及治疗方法，科学家们利用动物模型进行研究，阿尔茨海默病动物模型的构建方法及应用也因此变得极为重要。

1. 构建阿尔茨海默病动物模型的方法常用的动物模型有老鼠、大鼠、狗、猪和猴子等。

其中，以老鼠模型为例，构建方法主要分为以下几步：（1）选择适合的老鼠品种。

根据研究目的，选择适合的老鼠品种。

常用的AD模型老鼠品种有Tg2576、APP/PS1、3xTg-AD、5xFAD等。

（2）转基因。

将人类AD相关基因转化到老鼠基因组中，构建“人类化”老鼠模型。

常用的基因包括APP、PS1、Tau等。

（3）验证模型。

通过行为学和病理学等方面的验证，确认AD模型老鼠是否符合预期。

2. 阿尔茨海默病动物模型的应用（1）病理生理学研究。

通过构建AD动物模型，可以对AD发病机制进行深入研究，例如beta淀粉样蛋白的形成、Tau蛋白的异常聚集等。

（2）药物研发。

利用AD动物模型，可以筛选和评价抗AD药物，例如Aβ清除剂、Tau蛋白抑制剂等。

（3）治疗研究。

通过构建AD动物模型，可以研究各种治疗方法的有效性，例如基因治疗、细胞治疗等。

（4）影像学研究。

通过AD动物模型，可以研究AD病理变化对脑部结构和功能的影响，例如磁共振成像、PET等技术。

阿尔茨海默病动物模型的构建方法及应用是AD研究中非常重要的一部分。

通过构建AD动物模型，可以更好地研究AD的发病机制和治疗方法，为AD的临床治疗提供理论和实践依据。

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UNLV Theses/Dissertations/Professional Papers/Capstones12-1-2010Donepezil and galanin interactions in an animalmodel of Alzheimer’s disease

Jonathan J. SabbaghUniversity of Nevada, Las Vegas

Follow this and additional works at:http://digitalscholarship.unlv.edu/thesesdissertationsPart of theNervous System Diseases Commons,Neurosciences Commons, and thePathologyCommons

This Thesis is brought to you for free and open access by Digital Scholarship@UNLV. It has been accepted for inclusion in UNLV Theses/Dissertations/Professional Papers/Capstones by an authorized administrator of Digital Scholarship@UNLV. For more information, please contactmarianne.buehler@unlv.edu.

Repository CitationSabbagh, Jonathan J., "Donepezil and galanin interactions in an animal model of Alzheimer’s disease" (2010).UNLV Theses/Dissertations/Professional Papers/Capstones.Paper 771. DONEPEZIL AND GALANIN INTERACTIONS IN AN ANIMAL MODEL OF ALZHEIMER’S DISEASE

by Jonathan Jacob Sabbagh Bachelor of Science Tulane University 2004

A thesis submitted in partial fulfillment of the requirements for the

Master of Arts in Psychology Department of Psychology College of Liberal Arts

THE GRADUATE COLLEGE We recommend the thesis prepared under our supervision by Jonathan Jacob Sabbagh entitled Donepezil and Galanin Interactions in an Animal Model of Alzheimer’s Disease

be accepted in partial fulfillment of the requirements for the degree of Master of Arts in Psychology

Jefferson Kinney, Committee Chair Daniel Allen, Committee Member Laurel Pritchard, Committee Member Frank van Breukelen, Graduate Faculty Representative

Ronald Smith, Ph. D., Vice President for Research and Graduate Studies and Dean of the Graduate College

December 2010 iii

ABSTRACT Donepezil and Galanin Interactions in an Animal Model of Alzheimer’s Disease by Jonathan Jacob Sabbagh Dr. Jefferson Kinney, Examination Committee Chair Assistant Professor of Psychology University of Nevada, Las Vegas

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by a progressive loss of cognitive function. One of the neurobiological hallmarks of AD is a progressive loss of cholinergic neurons and a decrease in the amount of acetylcholine in the brain. Pharmacological therapies have targeted the cholinergic system, specifically first-line, palliative treatment using acetylcholinesterase (AChE) inhibitors, such as donepezil. Donepezil has been shown to increase cholinergic tone and ameliorate some of the cognitive deficits in AD patients. Galanin, a neuropeptide that inhibits the evoked release of several neurotransmitters including acetylcholine as well as modulates seveal intracellular cascades, is overexpressed in AD resulting in an as yet unidentified modulation of neurobiological function. Galanin also impairs learning and memory when administered centrally to rodents, suggesting it may contribute to the cognitive impairments observed in AD. While the mechanism by which galanin impairs learning has yet to be determined, studies suggest it is through cholinergic mechanisms. We investigated the ability of donepezil to rescue learning and memory deficits induced by galanin administration, and by extension isolated whether the learning impairments produced by galanin were ameliorated by increasing cholinergic tone. We also investigated the effects of donepezil and galanin in an animal model of AD, i.e. their iv

effects on learning and memory following a slight lesion of cholinergic neurons analogous to the cholinergic loss seen in AD. This study provides vital information about the relationship between galanin-induced deficits and acetylcholine, and helps to clarify the roles of donepezil and galanin in AD. v TABLE OF CONTENTS ABSTRACT ....................................................................................................................... iii

CHAPTER 1 INTRODUCTION ................................................................................... 1 Research Questions ..................................................................................................... 6

CHAPTER 2 REVIEW OF RELATED LITERATURE ............................................... 9 Amyloid β Hypothesis ................................................................................................ 9 Tau Hypothesis ......................................................................................................... 17 Cholinergic Hypothesis ............................................................................................. 20 Excitotoxicity Approach ........................................................................................... 26 Galanin Literature ..................................................................................................... 28 Hypothesis and Implications ..................................................................................... 34