University of Groningen

Microglia phenotypes in aging-associated diseasesYin, Zhuoran

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Publication date:2017

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Citation for published version (APA):Yin, Z. (2017). Microglia phenotypes in aging-associated diseases. [Groningen]: University of Groningen.

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Nederlandse samenvatting / Dutch Summary

Acknowledgement

Curriculum vitae

C H A P T E R 7

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NEDERLANDSE SAMENVATTINGVerbeteringen met betrekking tot de gezondheidszorg hebben er toe geleid dat de levensverwachting van de mens de laatste jaren aanzienlijk is gestegen, met een toename van ouderdomsziektes tot gevolg. Verouderings-gerelateerde veranderingen in het centraal zenuwstelsel (CZS) omvatten morfologische veranderingen en functionele achteruitgang, alsmede een toename van neurodegeneratieve ziektes. Ook zien we neuroinflammatie toenemen in het verouderende brein, en dit fenomeen zou het verschil kunnen maken tussen gezond oud worden en het ontstaan van neurodegeneratieve ziektes. Microglia, de immuuncellen van het CZS, zijn de hoofdrolspelers in deze neuroinflammatoire processen. Het doel van dit proefschrift is om de fenotypische en morfologische veranderingen in microglia te beschrijven in ouderdoms-gerelateerde neurodegeneratieve ziektes. In hoofdstuk 2 bestuderen we microglia in 5xFAD en APP23 muizen, twee muizenmodellen voor de ziekte van Alzheimer (AD). We beschrijven de aanwezigheid van hyperreactieve microglia in de nabijheid van Aβ plaques na inductie van een systemische ontsteking en uit genexpressie onderzoek van deze microglia blijkt dat genen die een rol spelen in AD, zoals immuunrespons, cel beweeglijkheid en cel differentiatie, verhoogd tot expressie komen. Ook vergeleken we plaques van donoren met ouderdoms-gerelateerde AD met plaques van juveniele AD donoren. Hier vonden we vooral in juveniele AD donoren een verhoging van fagocytose genen en AD gerelateerde genen. In de AD pathologie lijken juist deze Aβ-plaque geassocieerde microglia de primaire oorzaak te zijn van neuroinflammatie. In hoofdstuk 3 wordt het genexpressie profiel van microglia uit hersenen van oude en jonge muizen met elkaar vergeleken en tonen we aan dat het profiel van ‘oude microglia’ duidelijk afwijkt. Vooral in de witte stof van oude muizen zien we een verhoogde expressie van genen die een rol spelen bij pro-inflammatoire processen, vet recycling en fagocytose. In humane post mortem hersenmonsters zagen we al beginnende neuroinflammatie in de witte stof van donoren van middelbare leeftijd en blijkt in de witte stof van oude donoren en donoren met juveniele AD neuroinflammatie dominant aanwezig. Wij concluderen dat neuroinflammatie kan bijdragen tot de progressie van neurodegeneratie en een voorspellende waarde kan hebben met betrekking tot de eerste symptomen en de progressie van hersenveroudering en neurodegeneratie.

Hoofdstuk 4 beschrijft het effect van een dieet met hoog vetgehalte (HFD) op microglia. In HFD muizen ondergaan deze cellen morfologische veranderingen en is er een toename van proliferatie in de cortex, hypothalamus en cerebellum. Echter, de verandering van dieet had geen invloed op de reactie van microglia na een i.p. injectie van lipopolysacchariden (LPS) afkomstig uit de bacteriële celwand. Een dieet met

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laag vetgehalte (LFD) in combinatie met calorische restrictie leidt tot een verlaging van expressie van fagocyterende genen in witte stof microglia van ouder wordende hersenen. Deze studie toont de beschermende rol van calorische restrictie gedurende veroudering aan. Hoofdstuk 5 beschrijft de neuromusculaire symptomen in een nieuwe transgene muizenstam met tauopathie. In deze muizen vindt een verhoogde neuron-specifieke expressie van P301S mutante eiwit Tau plaats. Drie maanden na geboorte vertoont deze Tau 58/4 muis al problemen met het motorische systeem en dit verslechtert gedurende veroudering, met bijkomende symptomen als beschadiging van de zenuwverbindingen en verschrompeling van de kuitspier Musculus extensor digitorum longus. Met behulp van elektronenmicroscopie zagen we ultra-structurele veranderingen in de sciatische zenuw, hetgeen een aanwijzing geeft voor het verlies en beschadiging van grote zenuwvezels. Tevens zagen we een verhoging van glia activiteit in de betreffende zenuwvezels van het ruggenmerg van deze muizen. We concludeerden dat de accumulatie van hypergefosforyleerde tau eiwitten in zenuwuiteinden veranderingen in de witte stof, beschadiging van de zenuwverbindingen en spieratrofie veroorzaakt. Al deze waarnemingen zijn waarschijnlijk verantwoordelijk voor de verslechtering van de motor functie in deze Tau58/4 muizen.

Immuun hyperreactiviteit in Aβ-plaque geassocieerde microglia

Er is al lange tijd een discussie gaande over de functie en het fenotype van microglia uit de directe nabijheid van Aβ-plaques. In hoofdstuk 2 beschrijven we verhoogde expressie van fagocytose - en AD-geassocieerde genen, zoals Axl, MHC II/HLA-DRa, Apoe, Trem2 en TyroBp in microglia uit de directe nabijheid van Aβ-plaques in AD muizenmodellen en in post mortem hersenweefsel van juveniele Alzheimer patiënten. De uitscheiding van het cytokine IL-1β is substantieel verhoogd in microglia uit de directe nabijheid van Aβ-plaques van APP23 en 5xFAD muizen na een i.p. LPS injectie. Het genexpressie profiel van MHCII+ microglia (representatie van microglia uit de directe nabijheid van Aβ-plaques) toont aan dat de versterkt gereguleerde genen betrekking hebben op biologische processen aangaande “immuun response op een externe stimulus” (b.v., Axl, CD63, Egr2 en Lgals3), “cel beweeglijkheid” (b.v., Ccl3, Ccl4, Cxcr4 en Sdc3), “differentiatie” en “systeem ontwikkeling” (b.v., St14, Trpm1 en Spp1). Onze resultaten wijzen uit dat microglia rondom Aβ-plaques een pro-inflammatoir fenotype bezitten.

Toename van inflammatie in de witte stof van hersenen van ouderen en patiënten met de ziekte van Alzheimer

Uit MRI studies komt naar voren dat de witte stof in de hersenen gevoelig is voor zijn verouderende omgeving. Aantasting van de witte stof is ook beschreven in juveniele

Alzheimer patiënten en manifesteert zich zelfs eerder dan de beschadiging in de grijze stof. In hoofdstuk 3 onderzochten we de fenotypische en functionele veranderingen van witte stof microglia in de context van het ouder wordende brein en in AD. Microglia uit witte stof van oude muizen brengen specifieke ‘fagocytose genen’ tot expressie (b.v., Mac-2, Axl, CD16/32, Dectin1, CD11c en CD36). Bij een vergelijking van microglia uit witte en grijze stof bleek dat de RNA expressie van facocytose- en activatie markers (b.v., Axl, CD36, Clec7a, LgalS3 en ApoE) significant hoger waren in witte stof microglia van oude muizen. In humane post mortem hersenmonsters worden de eerste symptomen van microglia activatie al gezien vanaf middelbare leeftijd en vindt dit voornamelijk plaats in de witte stof en in juveniele Alzheimer patiënten. Microglia activatie in de witte stof kan in de toekomst mogelijk een prognostische waarde hebben met betrekking tot de signalering van de aanzet van het ouder wordende brein en neurodegeneratie.

Onderdrukking van ontstekingsprocessen in de oudere hersenen door een dieet met laag vetgehalte in combinatie met calorische restrictie.

Het is bekend dat diermodellen voor het bestuderen van veroudering en obesitas worden gekarakteriseerd door ontstekingen in bepaalde hersengebieden, waaronder de hypothalamus. In hoofdstuk 4 onderzochten we microglia fenotypes in de verschillende hersengebieden van muizen met een dieet met een hoog - (HFD) en laag vetgehalte (LFD). Een HFD zorgt voor een toename van het aantal microglia en een toename van het oppervlak van het microglia cellichaam in de cortex, hypothalamus en cerebellum. We zagen geen verschil in expressie profielen van genen die betrekking hebben op de immuunrespons, fagocytose en metabolisme tussen microglia afkomstig uit de hypothalamus van jonge HFD en LFD muizen. De expressie van fagocytose genen was daarentegen aanzienlijk gedaald in LFD muizen met calorische restrictie, wat duidt op een beschermende rol van calorische restrictie gedurende veroudering. Concluderend, calorische restrictie is een niet-genetische interventie met een positief effect op de verouderende brein.

CONCLUSIEWij hebben onderzoek gedaan naar de fenotypische en functionele veranderingen van microglia in relatie tot verouderings-gerelateerde ziektes. Gebaseerd op dit onderzoek kunnen we speculeren dat verkeerd gevouwen eiwitten, specifieke omgevingsfactoren van de hersenen en dieet veranderingen een effect kunnen hebben op het fenotype van microglia in de context van veroudering en neurodegeneratie. Wij stellen dat hyperreactive microglia rondom Aβ-plaques en de toename van microglia activatie in de witte stof van de ouder wordende hersenen en AD hersenen een potentiele

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rol kunnen spelen bij het onderzoek naar diagnostische en therapeutische targets. Calorische restrictie lijkt effectief als bescherming tegen de ouder wordende brein, aangezien een dieet met een laag vetgehalte in combinatie met calorische restrictie voor ‘rustiger microglia’ in de witte stof zorgt.

Acknowledgement

ACKNOWLEDGEMENT

Doing a Ph.D. is an important and necessary training for creative thinking, independent research, and scientific perspective. I feel extremely grateful and lucky that I could pursue my Ph.D. degree in Department of Neuroscience, UMCG. Although there were several tough times, with all the help and support, I learned knowledge, obtained various experiences, and managed to finalize the thesis. The life in the Netherlands also gives me valuable experiences. Here, I would love to express my sincere gratitude to all those who helped and supported me over the years, because you build the beautiful memories for me.

First and foremost, I would like to acknowledge my promotor Prof. Dr. Erik Boddeke and co-promotor Dr. Bart Eggen. Dear Erik, when I was still in China, I had the dream to become a neurologist and to do valuable research in future. Thank you for initiating the wonderful journey for me, which took me from the city besides Yangtze River to Groningen. Because of your patience and trust, I could learn fast and practice a lot without any stress. I still remember the trip that you drove me to Antwerp. You told me that I could go further, which has motivated me up till now. Thank you for letting me go to Antwerp, Goettingen, and Munich for collaborative work, where I learned a lot from international collaborators and obtained wonderful experiences. Under your supervision, I learned knowledge, experience, and scientific perspectives. You are always working very hard. Sending and receiving working emails with you in the midnight let me see your dedicated attitude towards science. The suggestions you give me about my future taught me to have a big picture and make wise decisions. Of course, it is also very nice to talk about music, the eight sheep and naughty chicken with you. Thank you for everything. I will go further and further. You are always my super boss.

Dear Bart, I am truly inspired by your wonderful tastes on research and your fruitful ideas. Thank you for your wise suggestions on the experimental design and scientific writing. I admire your practical way of thinking about the research. Your office door is always open for scientific discussion. I am also inspired by your everlasting enthusiasm on the cutting-edge research. Thank you for your constant encouragement during these years. You are always humorous and optimistic. Talking with you and listening to your nice jokes bring me relief. Let us keep in touch and look forward to continuing collaborations.

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I would like to thank China Scholarship Council for the financial support and her collaboration with the University of Groningen, which gives me the chance to pursue the scientific training.

Dear Jon, I always enjoy the scientific discussions with you, and I am inspired by your theoretical perspectives. Your support for the project of HFD/LFD animals taught me a lot, e.g., making a practical plan, summarizing from each discussion, making constructive items for the draft. Thank you for your advice on the experimental design and writing. Especially, you spent quite some personal time on helping the Ph.D. students improve our presentation skills. This is very important for the academic development of young researchers. Thank you for your everlasting support and encouragement. Hope to keep in touch with you and to have further collaborations.

I would like to acknowledge the members of the assessment committee: Prof. Dr. Thomas Bayer, Prof. Dr. Peter P. De Deyn, and Prof. Dr. Sophia de Rooij for carefully reading and approving my thesis.

I would love to thank our collaborators from University of Antwerp, Belgium: Prof. Dr. Peter P. De Deyn, Dr. Debby van Dam, and Femke Valkenburg. Dear Prof. De Deyn, I am very lucky to have the opportunity to work in your lab. These transgenic animal models and human post-mortem samples from IBB are very valuable for the projects. The collaborative atmosphere in your lab also gives me a lot of support during the years. Without your help, these projects can’t happen. Every time when I present our data, you always kindly and patiently give feedback, which encourages me a lot. If I could follow you to do nice clinical work and valuable research, that will be fantastic. Hope to keep in touch with you and I wish this may come true in future. Dear Debby, thank you for all your help in Antwerp. Every time I went to Antwerp, it took you a lot of energy to organize and prepare the mice. Thank you for providing valuable suggestions for designing the experiments and writing the paper. I feel very happy that our hard work ends up with the data in chapter 2, 3, and 5. Dear Femke, it is very nice to work with you for the Tau mice project. You are precise, efficient, energetic, and very helpful. I am very happy that the paper got accepted. Wish you all the best in the future.

I also want to thank the collaborators from University Medical Center Goettingen, Germany: Prof. Dr. Thomas Bayer, Prof. Dr. Uwe-Karsten Hanisch and Dr. Nasrin Saiepour. Dear Prof. Bayer, thank you for being my reading committee and kindly

sharing the animal samples of 5XFAD mice. I hope we can continue collaborating in the future. Dear Uwe, thank you for providing me the opportunity to let me work in your group. Thank you for all the suggestions and encouragement you gave me. Although you couldn’t see this thesis any more, I will always remember this. Dear Nasrin, you are such a kind, helpful, and considerate girl. It was very nice to meet you and working together in Goettingen. Thank you for letting me stay in your place and showing me around. Do you remember the nice shop for wedding dresses? It was a very special moment for us. Hope we could keep in touch, welcome to China and hope to meet you again.

I would love to thank the collaborators from the Department of cell biology, UMCG, Prof. Dr. Fulvio Reggiori, Dr. Muriel Mari, and Xingdong Zhou. The generated data were described in chapter 5. Dear Fulvio, thank you for nicely allowing the collaborations with us. Dear Muriel, I learned a lot from your attitude and your expertise. Hope that we could collaborate in future. Dear Xingdong, thank you for your patience and effort. I wish all the best for you in future.

I would love to thank the collaborators, Prof. Dr. Elly Hol and Dr. Willem Kamphuis. Dear Prof. Hol and Willem, thank you for kindly providing the animal samples of APP/PS1 mice.

Many thanks to the collaborators from Lundbeck, USA, Dr. Thomas Möller, Dr. Joseph Tamm, and Aicha Abdourahman. It was a pleasant international collaboration. I am very happy that the generated data was part of chapter 2.

My appreciation for the collaborators for the project on HFD/LFD animals: Dr. Roel van der Heiden, Aaffien C. Reijne, Dr. Jill Moser, Prof. Dr. Peter Heeringa, Dr. Chunxia Yi, and Prof. Dr. Gertjan van Dijk. Dear Chunxia, thank you for providing the opportunity to let me and Divya work in Munich. It was unforgettable experience. Dear Yuanqing, thank you for your help and it was very nice to visit the center of Munich with you. Best wishes with everything!

My thanks also go to the collaborators, Prof. Dr. Sandra Amor, Marjolein Breur and Dr. Janine Doorduin, for the project on white matter. Dear Sandra, thank you for giving me the opportunity to perform the experiments in your lab and thanks for your advice on my writing. Dear Marjolein, it was nice to perform the experiment in

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Amsterdam with you. Thank you for your nice and clear explanations. Dear Janine, it was fun to have the neuroanatomy course with you. Best wishes with everything and hope for continuing collaborations.

I would love to thank Dr. Wilfred Den Dunnen. in the beginning of this paragraph. Dear Wilfred, for the white matter project and tau project, you spent your time kindly on discussing these projects with me and helping me arrange the samples. During our discussion, thanks for your patient explanation, I learned to look at the research question with a clearer and more straightforward perspective, then to look for solutions focusing on the research question. Thank you for all the help. Hope to keep in touch and look forward to continuing collaborations.

Dear Nieske, during the past years, I have learned a lot from your way of making practical plans, looking for solutions, and thinking positively. At the beginning of my Ph.D., you taught me patiently and trained me with techniques. Then I am inspired by your dedicated and passionate attitude towards work. I will always remember our trips to Antwerp, Den Haag, and Amsterdam. I still can recall the scenes that we were sweating in an Antwerp bus stop with a lot of experimental materials under the sun, or we cycled happily to the center of Antwerp. It was nice that you explained the Victory Boogie Woogie to me. They are all wonderful parts of my Ph.D. journey. When my mother came to Groningen, thank you and Jan for inviting us to your place for a nice dinner. You are warm-hearted and considerate for the international students. Jan and you organize the nice party for New Year’s Eve when all the international students gathered in your place. Thank you for a lot of encouragement when I face the failures of the experiments. The photo that you took for me in Amsterdam is very sweet and is always standing in my parents’ house. Sometimes I feel that you support and treat me like a mother, which warms me and gives me a lot of strength. I feel so blessed to meet you in Groningen. Words are not enough for me to express my gratitude. Best wishes for all your family. Welcome to China, hope to see you again, and let us keep in touch.

Dear Sjef, you are a wise, critical, and humorous scientist. I learned a lot from you during the scientific discussions in the work meetings. Thank you for your suggestions when we talked about the project of tau mice. Best wishes for your family and wish you to enjoy a great retirement.

Dear Amagan, I always admire your professional achievement, kindness, happiness, and balanced life. Your beautiful smiles and thoughtful words could cure a lot of things. As a female and a scientist, you are really great! Best wishes for your family!

Dear Rob, you are very wise, kind, and patient. It is interesting to talk about some educational or political topics with you. Thank you for organizing the skating course for the foreign students of the lab. I believe in future I could skate . Dear Inge, I learned a lot from the discussion with you about the statistical problems. Thank you for the nice and clear explanations. Best wishes with everything!

Dear Knut, you are very wise, kind and have a wonderful taste on research. Thank you for your suggestions on the project of plaque-associated microglia. Best wishes for everything!

I would like to acknowledge our secretary Trix. Thank you for arranging documents and solving problems during these years. With your help, my life here becomes much easier.

Dear Ietje, thank you for all your help in the immunohistochemistry. In order to help me, you adjust your working time or prolong your working hours. You are always patient and so experienced in immunohistochemistry. It is also full of fun to speak Dutch with you and talk about your lovely grandchildren. I appreciate that you love your life a lot, like yoga, gardening, children… Hope you could always keep young, be happy with family life and enjoy the wonderful life.

Dear Eef, you are organized, warm-hearted, and sweet. During the past years, I saw you falling in love, getting married, and having wonderful babies. Great achievements! Especially, I could see how happy you are now. I feel so happy for you. Best wishes for your family, especially Hugo and Liek .

Dear Hilmar, thank you for your nice explanations for the Sholl analysis and all the suggestions for the figures and the thesis cover. Dear Suus, I am always willing to listen to your opinions during the scientific discussions. You are very talented and professional. It is also nice to talk about the babies with you, which I am still at the preliminary/theoretical stage . Best wishes for you, Hilmar, and two lovely girls.

Dear Michel, thank you for helping me with the microscopy. It is very impressive to see the films that you made for the work and also from nature. Best wishes for everything. Enjoy the love !

Dear Tjalling, thank you for all the technique support during all these years. When I was the paranymph of Inge, thank you for helping me making the song for Inge.

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I would also love to thank a lot of colleagues in the section of Medical Physiology, Harry Moes, Henk Heidekamp, Dr. Hiske van Duinen, Dr. Wieb Patberg, Annelies van de molen. Dear Henk and Harry, thank you for arranging several documents and solving problems for me.

I would love to acknowledge Klaas Sjollema for the technique support for microscopy. I would love to acknowledge the support in the FACS facility: Geert Mesander, Roelof Jan van der Lei, and Henk Moes in UMCG, and Dr. Natalie Cools in the University of Antwerp.

I would also like to thank Ph.D. and postdocs who worked before or are now working in the department: Xiaoming Zhang, Divya Raj, Clarissa Haas, Inge Holtman, Ilia Vainchtein, Marissa Dubbelaar, Wandert Schaafsma, Ria Wolkorte, Koen van Zomeren, Duco Schriemer, Claudio Tiecher, Arun Thiruvalluvan, Leroy Schreuder, Javier Gustavo Villamil Ortiz, Malte Borggrewe, Laura Kracht, Roeland Prak, Kumar Balasubramaniyan, Susanne Kooistra, Corien Grit, Rianne van der Pijl, Suping Peng, Zhilin Luan, Yang Heng, Thaiany Quevido Melo, Thais Galatro.

Dear Xiaoming, you are always kind, helpful, reliable, and tough. It is lucky to become Chinese allies with you . You have got great achievement during the past four years and I believe you will have a fruitful Ph.D. Thank you for your help in the designing and doing experiments. It is always nice to work with you together. Good luck with everything and all the best for you, Ping, Zidong, and Hengrui in future. Let us keep in touch and hope to see you again!

Dear Divya, I still remember the first day I met you. You explained and showed brain tissues for me. How time flies! You are very smart, creative, warm-hearted, and have a nice nature. We worked very hard together in Antwerp and Munich. It was encouraging to discuss scientific questions with you. Thank you for the Indian dinners that you prepared for me. They were nice and delicious. Thank you for all the help during my Ph.D. Best wishes for your family and enjoy being a happy mother .

Dear Duco, it is nice to be your desk mate for three years. You are patient and always willing to help. You also live a life of self-discipline, which I admire a lot. In most cases, you were very calm . Thank you for patiently answering my questions when I learned Dutch. By the way, your skills of making furniture are fantastic! Best wishes to you with everything.

Dear Mingsan, it was nice to be your office mate. You were very busy and worked hard, but you always tried to help others. Thank you for sending the DVD “the gifted hand” to me as a present. Maybe that is a dream for every doctor. I have a lot of fun in board-game evenings with you, Suping, Liwen, Betty, and Ilia.

Dear Ilia, you helped me in many ways. Thank you so much for your suggestions for the experiments. I admire your way of organizing and arranging. You are very important in the glia group and could be the model for the junior Ph.D. student. You have a very nice nature and are warm-hearted. It is always nice to talk with you and to have dinner and game night within our board game group. I hope you could go on developing your curiosity in both science and the wonderful life. Best wishes for your future and let us keep in touch!

Dear Inge, I admire in many traits of you. You are smart, brave, straightforward, and efficient. You are also considerate and willing to help others. Having dinner and going to party with you are the wonderful parts of my Ph.D. period. It was also a nice experience to be your paranymph. I miss you these days. Best wishes for you in the US. Let us keep in touch and hope to meet you again.

Dear Claudio, you are a considerate and nice guy. In most cases, you are relaxed. Talking with you could bring me a lot of relief. Hope to talk with you when you come back from Japan. It must be a lot of fun!

Dear Yang, it is and will still be a wonderful journey for you in Groningen as a Ph.D. student. Thank you for helping the cover designing and hope you to explore more interests (e.g., guitar) in the coming years and enjoy the life here. Good luck with everything!

Dear Corien, you are sweet, honest, and warm-hearted. I feel really relaxed every time that I talk with you. It was a nice memory to go to Goettingen with you, Rianne, and Doortje. Best wishes for everything. Hope all your projects go well. I believe you will make great achievements when you finish your Ph.D.

Dear Rianne, you are a warm, nice and pretty girl. The cake that you made for us is not only delicious, but also with your heart. Every cloud has a silver line. Believe yourself ! All the best for your future.

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Dear Roeland, it is lucky to have you as my office mate. You are very smart and focused. It is nice to discuss the experience of studying medicine and doing research with you. I could find nice common points with you. Good luck with your project and best wishes with everything.

Dear Laura, you are calm, beautiful, and joyful. I feel peaceful and happy every time when I talk with you. Good luck with everything and have a wonderful life!

Dear Arun, we worked four years in the same office. You are really good and precise in doing experiments. It is nice to discuss scientific questions with you. You love and enjoy the life, e.g., sports, traveling, and organizing parties. Thank you for inviting us to the Diwali event and to experience the Indian culture. Best wishes to you.

Dear Malte, you always look calm and peaceful. You bring a lot of fun to our group. Best wishes and good luck with everything!

Dear Wandert, you have a very nice nature. You are smart, optimistic, and relaxing. Thank you for all the help. I am happy to work with you for the HFD project and hope it will go well. Best wishes for your life in Spain and good luck for the wine business.

Dear Koen, you are really a generous and brave guy. The winter Marathon in Apeldoorn with Michel, Duco, Sabrina, and Inge will always in my memory. A lot of thanks for your parents for the nice dinner that your mother cooked. Dear Sabrina, you are sweet, energetic, and nice. Your smile is very warm and pure. We kept together to run to the end of the Marathon. I will always remember that. All the best wishes for you and Koen. Welcome to China and hope to travel together.

Dear Alain, you are very smart and dedicated. You show a strong motivation in the research of Down syndrome, which is very impressive. You are also humorous, knowledgeable, and warm-hearted. We had several interesting talks. I hope you could become a great scientist in future and hope for continuing collaborations.

Dear Javier, you are kind, humorous, and friendly. The research that you are doing are also interesting. Good luck with everything and enjoy the wonderful life here.

Dear Eline, it was nice to be your desk mate, although the time is not long. Thank you very much for spending your time on adjusting my Dutch pronunciations. Best wishes with everything!

Dear Doortje, you are always sweet, patient, and warm-hearted. It was nice to work with you for immunohistochemistry. Thank you for the chocolate. It was a big and nice surprise for me .

I would also acknowledge my student, Betty Hornix. Dear Betty, it was nice to work with you. You are considerate, dedicated, and creative. Thank you very much for your help with the tau mice project, and now it nicely becomes a paper. A lot of thanks for answering many questions about the Dutch language from me . Wish you to have a happy and wonderful life as a Ph.D. and all the best for your future.

Special thanks to my paranymphs: Clarissa Hass and Marissa Dubbelaar. It is a great pleasure to have you as my paranymphs. Dear Clarissa, you are very sweet, pure, and thoughtful. You are one of the persons I like to turn when I want to talk. I am impressed by the delicious Brazilian food that you made. I enjoy the time that we spent together during the lunch time. Now the Ph.D. life may be a bit tough for you. But I believe you will get through it soon. Best wishes with everything. Dear Marissa, you are smart, collaborative, and efficient. Every time I talk with you, I could feel the optimism and happiness from you. Now it is very nice of you to organize colleagues for a lunch walk. Thank you two for your help and I wish I can have the chance to show you some parts of China. Welcome to China!

I would love to thank all the Chinese friends who I met during my Ph.D. study in the Netherlands: Qi Wang, Liwen Zhang, Bing Han & Haoxiao Zuo, Ting Zhao & Yi Jiang, Zhe Sun & Jing Qin, Xiaoming Zhang & Ping Xu, Yuanze Wang & Jingjing Deng, Tao Zhang & WenJuan Wang, Zhuozhao Zhan, Zhilin Luan, Suping Peng, Yang Heng, Yixian Li, Yingying Cong, Xingdong Zhou, Peng Wang, Rui Yan, Ye Yuan, Qi Cao, Jun Li, Qi Xu, Chengtao Ji, Xiaohong Han, Xingchen Yan, Shengcheng Ren, Yuzhen Qin, Yehan Tao, Han Guo, Bin Liu, Huala Wu, Haigeng Fu, Mingming Shi, Jiacong Wei, Yuan He, Yuan Wang, Cuifeng Wang, Rui Wu, Juan Song, Peng Sun, Hefeng Zhou, Ming Li, Xiang Zeng, and many others who I may forget to mention here. All of you are one important part in my life in the Netherlands. Dear Qi and Liwen, my nice roommates, every time when I come back from hard work, cooking food and chatting together with you would comfort me a lot. Thank you for letting me feel like at home. Look forward to meeting you in future. I also hope you to enjoy your life and good luck with everything. Dear Ting, it is nice to talk with you and thank you. Enjoy your sweet life. Best wishes for your family! Dear Bin and Haoxiao, I feel so lucky to meet you guys here and thank you for all the help in Groningen and Goettingen.

Curriculum vitae

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Best wishes to you! Dear Zhilin, I will always remember the days we travelled together. They are colorful days in my life. It is nice that we could defend in the same day. Hope that we could visit each other in future and best wishes to your family!

我要感谢我的母校华中科技大学同济医学院和同济医院，感谢老师言传身教为

我打开科学的大门，让我志愿成为一名好医生和科研工作者。他们是邓又斌教

授，朱遂强教授，李开艳教授，陈晓钎教授，宋静老师以及许许多多帮助和指

导过我的老师。我要感谢一路求学所遇到的各位学长学姐和同学。感谢一路以

来结识的很多好朋友，和你们在一起度过了很多快乐的时光。

我要感谢我的爷爷奶奶，外公外婆在我成长的道路上所给予我的爱，支持与谆

谆教诲。我希望完成博士学位可以让在天堂的爷爷和外婆感到欣慰。我想要特

别感谢我的外公，不时给予我提点，寄望和充满智慧的话语，更言传身教，照

亮前方的路。感谢大姨，二姨，三姨，和叔叔，感谢姐姐妹妹和侄女侄子们，

是你们让我可以在温暖的大家庭里充满爱的生活。

在此，我要感谢我的先生杨开涛。我们可以在荷兰相遇使我相信缘分的力量，

非常感谢你的爱，支持与耐心。我们的生活即将迎来一位小宝宝，非常期待你

的到来，想要看看你的模样。

亲爱的爸爸妈妈，你们为我的成长倾注了太多的心血。从幼年时无微不至的爱

与陪伴，少年时风雨无阻的伴我求学，青年时全力支持我攻读医学院再到荷兰

攻读博士，一日一日直至三十年。恩情深重，常怀心中。非常爱你们。希望日

后我可以多多陪伴你们，健康快乐的生活下去。

Curriculum vitae        

Zhuoran  Yin was  born  on  January  the  22nd,    1987  in Wuhu,  Anhui  Province,  China.  She 

completed her secondary education  in Wuhu No. 1 Middle School.  In  the year 2004‐2011, 

she  studied  clinical  medicine  (7‐year  successive  program)  at  Tongji  Medical  College, 

Huazhong University of Science and Technology  (HUST), Wuhan.  In 2009, she obtained her 

Bachelor degree in Clinical Medicine. Subsequently, she performed her medical internship in 

Tongji Medical College affiliated Tongji Hospital.  In 2010‐2011, she did her master research 

project  “Impact  of  lesions  in MRI  examination  on  the  surgical  outcome  of  epilepsy”  in 

Department of Neurology, under supervision of Prof. Suiqiang Zhu. During her medical study, 

she  received  several honors  including  the National Scholarship of China, 1ST  scholarship of 

HUST, Outstanding Graduate Award of HUST. Upon obtaining her Master degree  in Clinical 

Medicine, Zhuoran worked as a resident in Tongji Hospital for 1 year. Then Zhuoran started 

her PhD study in Department of Neuroscience at University Medical Center Groningen under 

the  supervision  of  Prof.  Dr.  H.W.G.M.  (Erik)  Boddeke  and  Dr.  Bart  J.L.  Eggen.  Here  she 

worked on microglia phenotypes  in animal models and human  samples  for healthy aging, 

Alzheimer’s disease, tauopathies, and obesity. The results of her PhD study are presented in 

this thesis. 

 

Scan below to access author’s LinkedIn page. 

 

CURRICULUM VITAEZhuoran Yin was born on January the 22nd, 1987 in Wuhu, Anhui Province, China. She completed her secondary education in Wuhu No. 1 Middle School. In the year 2004-2011, she studied clinical medicine (7-year successive program) at Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan. In 2009, she obtained her Bachelor degree in Clinical Medicine. Subsequently, she performed her medical internship in Tongji Medical College affiliated Tongji Hospital. In 2010-2011, she did her master research project “Impact of lesions in MRI examination on the surgical outcome of epilepsy” in Department of Neurology, under supervision of Prof. Suiqiang Zhu. During her medical study, she received several honors including the National Scholarship of China, 1ST scholarship of HUST, Outstanding Graduate Award of HUST. Upon obtaining her Master degree in Clinical Medicine, Zhuoran worked as a resident in Tongji Hospital for 1 year. Then Zhuoran started her PhD study in Department of Neuroscience at University Medical Center Groningen under the supervision of Prof. Dr. H.W.G.M. (Erik) Boddeke and Dr. Bart J.L. Eggen. Here she worked on microglia phenotypes in animal models and human samples for healthy aging, Alzheimer’s disease, tauopathies, and obesity. The results of her PhD study are presented in this thesis.

Scan below to access author’s LinkedIn page.

Curriculum vitae