阿茲海默氏症是一種漸進式的神經退化性疾病，然而至今沒有任何治療方法可以減緩阿茲海默氏症的病程發展，因此何種因子參與其中可以防止記憶衰退是我們研究的首要課題。過往相關研究指出，人類T細胞淋巴瘤侵襲和轉移蛋白2 (TIAM2)在神經發育中有著重要的作用。TIAM2有兩種RNA異構體，分別為全長(TIAM2L)和短片段(TIAM2S)異構體。曾有研究指出在人類組織中無法檢測到TIAM2L蛋白的存在，但卻發現TIAM2S蛋白在人類腦部含量特別豐富，尤其是高度表現在海馬迴中，並能促進神經突生長。然而，目前TIAM2S在阿茲海默氏症上有何種功能尚不清楚。為了研究TIAM2S基因的表現對阿茲海默氏症相關的認知缺陷之潛在影響，我們將3xTg-AD基因轉殖鼠與帶有人類TIAM2S的基因轉殖鼠進行交配，建立攜帶人類TIAM2S基因的阿茲海默氏症小鼠模型(3xTg-AD/TIAM2S小鼠)。在本研究中，我們發現相較於3xTg-AD小鼠，3xTg-AD/TIAM2S小鼠的海馬迴中TIAM2S表現量顯著升高，且認知功能有明顯提升。接著，我們進一步探討調控海馬迴中TIAM2S表現量是否會影響阿茲海默氏症相關的認知功能，我們分別將TIAM2S shRNA或TIAM2S cDNA注入小鼠的海馬迴中，以調控TIAM2S表現量。由結果顯示出，3xTg-AD/TIAM2S小鼠的海馬迴中TIAM2S表現量降低會破壞原先增強記憶的效果；而當海馬迴中TIAM2S表現量增加則可改善3xTg-AD小鼠的認知缺陷。除此之外，我們也發現，TIAM2S增加了3xTg-AD小鼠海馬迴中成熟形式腦源性神經滋養因子 (mBDNF)的表達，進而增強了神經可塑性。本研究結果將為阿茲海默氏症的研究開闢新的發展途徑，也為TIAM2S與阿茲海默氏症之間的關聯性提供新的見解。

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Until now, no treatments can slow down AD progression. Previous studies found that human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth. However, the functions of TIAM2S in AD are still unclear. To investigate the potential impacts of TIAM2S expression on AD-related cognitive deficits, we crossbred 3xTg-AD transgenic mice with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). In the study, we found that compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed increased hippocampal TIAM2S levels and improved cognitive functions. We further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether the manipulation of hippocampal TIAM2S expressions could affect AD-related cognitive functions. The results showed that the reduction of hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels could alleviate cognitive deficits in 3xTg-AD mice. Furthermore, TIAM2S increased mature brain-derived neurotrophic factor (mBDNF) expression and enhanced neuroplasticity in 3xTg-AD mice. These results will open new avenues for AD research and provide new insights into connecting TIAM2S with AD.

Adlimoghaddam, A., B. Roy, and B. C. Albensi. 2018. 'Future Trends and the Economic Burden of Dementia in Manitoba: Comparison with the Rest of Canada and the World', Neuroepidemiology: 71-81.
Alberini, Cristina M. 2009. 'Transcription factors in long-term memory and synaptic plasticity', Physiological reviews, 89: 121-45.
Alonso, Alejandra D., Leah S. Cohen, Christopher Corbo, Viktoriya Morozova, Abdeslem ElIdrissi, Greg Phillips, and Frida E. Kleiman. 2018. 'Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability', Frontiers in Cellular Neuroscience, 12.
Alzheimer's Association, . 2019. '2019 Alzheimer's disease facts and figures', Alzheimer's & Dementia, 15: 321-87.
Amin, Fakhra, Anas Shamsi, Muhammad Nadeem Asghar, Peerzada Shariq Shaheen Khaki, Mohd Shahnawaz Khan, Shams Tabrez, Syed Kashif Zaidi, Wajihullah Khan, and Bilqees Bano. 2019. 'Alzheimer’s: A Progressive Brain Disease: Causes, Symptoms, and Prevention.' in Ghulam Md Ashraf and Athanasios Alexiou (eds.), Biological, Diagnostic and Therapeutic Advances in Alzheimer's Disease: Non-Pharmacological Therapies for Alzheimer's Disease (Springer Singapore: Singapore).
Anand, K. S., and V. Dhikav. 2012. 'Hippocampus in health and disease: An overview', Ann Indian Acad Neurol, 15: 239-46.
Association, Alzheimer's. 2015. '2015 Alzheimer's disease facts and figures', Alzheimer's & Dementia, 11: 332-84.
———. 2018. '2018 Alzheimer's disease facts and figures', Alzheimer's & Dementia, 14: 367-429.
Bai, Yanyang, Xiaoliang Xiang, Chunmei Liang, and Lei Shi. 2015. 'Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac GEFs and GAPs', BioMed Research International, 2015: 632450.
Bakkour, A., J. C. Morris, D. A. Wolk, and B. C. Dickerson. 2013. 'The effects of aging and Alzheimer's disease on cerebral cortical anatomy: specificity and differential relationships with cognition', Neuroimage, 76: 332-44.
Bannerman, David M., Rolf Sprengel, David J. Sanderson, Stephen B. McHugh, J. Nicholas P. Rawlins, Hannah Monyer, and Peter H. Seeburg. 2014. 'Hippocampal synaptic plasticity, spatial memory and anxiety', Nature Reviews Neuroscience, 15: 181-92.
Bathina, S., and U. N. Das. 2015. 'Brain-derived neurotrophic factor and its clinical implications', Arch Med Sci, 11: 1164-78.
Beeri, Michal Schnaider, and Joshua Sonnen. 2016. "Brain BDNF expression as a biomarker for cognitive reserve against Alzheimer disease progression." In.: AAN Enterprises.
Bekinschtein, Pedro, Martin Cammarota, and Jorge H. Medina. 2014. 'BDNF and memory processing', Neuropharmacology, 76: 677-83.
Bird, Chris M., and Neil Burgess. 2008. 'The hippocampus and memory: insights from spatial processing', Nature Reviews Neuroscience, 9: 182-94.
Blank, Robert H. 2018. 'Alzheimer's Disease — Perspective from Political Science: Public Policy Issues', The Journal of Law, Medicine & Ethics, 46: 724-43.
Borba, Ericksen Mielle, Juliana Avila Duarte, Giovana Bristot, Ellen Scotton, Ana Luiza Camozzato, and Márcia Lorena Fagundes Chaves. 2016. 'Brain-derived neurotrophic factor serum levels and hippocampal volume in mild cognitive impairment and dementia due to Alzheimer disease', Dementia and geriatric cognitive disorders extra, 6: 559-67.
Bredesen, D. E., R. V. Rao, and P. Mehlen. 2006. 'Cell death in the nervous system', Nature, 443: 796-802.
Burgess, Neil, Eleanor A. Maguire, and John O'Keefe. 2002. 'The Human Hippocampus and Spatial and Episodic Memory', Neuron, 35: 625-41.
Cerejeira, Joaquim, Luísa Lagarto, and Elizabeta Mukaetova-Ladinska. 2012. 'Behavioral and psychological symptoms of dementia', Frontiers in neurology, 3: 73.
Chan, Y. L., W. C. Lai, J. S. Chen, J. T. Tseng, P. C. Chuang, J. Jou, C. T. Lee, and H. S. Sun. 2020. 'TIAM2S Mediates Serotonin Homeostasis and Provokes a Pro-Inflammatory Immune Microenvironment Permissive for Colorectal Tumorigenesis', Cancers (Basel), 12.
Chapman, D. P., S. M. Williams, T. W. Strine, R. F. Anda, and M. J. Moore. 2006. 'Dementia and its implications for public health', Prev Chronic Dis, 3: A34.
Charron, Yves, Jürgen Willert, Bettina Lipkowitz, Barica Kusecek, Bernhard G. Herrmann, and Hermann Bauer. 2019. 'Two isoforms of the RAC-specific guanine nucleotide exchange factor TIAM2 act oppositely on transmission ratio distortion by the mouse t-haplotype', PLOS Genetics, 15: e1007964.
Chen, Jia-Shing, Ih-Jen Su, Yu-Wei Leu, Kung-Chia Young, and H. Sunny Sun. 2012. 'Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer', International journal of cancer, 130: 1302-13.
Chiu, Choi-Ying, Song Leng, Kathleen A Martin, Esther Kim, Susan Gorman, and David MJ Duhl. 1999. 'Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1', Genomics, 61: 66-73.
Chu, Chun-Hsien, Jia-Shing Chen, Pei-Chin Chuang, Chia-Hao Su, Ya-Ling Chan, Ying-Ju Yang, Yu-Ting Chiang, Yu-Ya Su, Po-Wu Gean, and H. Sunny Sun. 2020. 'TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior', The FASEB Journal, 34: 3267-88.
Clayton, Kevin A., Alicia A. Van Enoo, and Tsuneya Ikezu. 2017. 'Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy', Frontiers in Neuroscience, 11.
Cunha, C., R. Brambilla, and K. L. Thomas. 2010. 'A simple role for BDNF in learning and memory?', Front Mol Neurosci, 3: 1.
Ding, Y., B. Chen, J. Huang, W. Zhang, H. Yang, Y. Deng, J. Lin, S. Wang, and X. Zhang. 2014. 'Overexpression of Tiam1 is associated with malignant phenotypes of nasopharyngeal carcinoma', Oncol Rep, 32: 607-18.
Diniz, Breno Satler, and Antonio Lucio Teixeira. 2011. 'Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond', Neuromolecular medicine, 13: 217-22.
Dubois, Bruno, Howard H Feldman, Claudia Jacova, Steven T DeKosky, Pascale Barberger-Gateau, Jeffrey Cummings, André Delacourte, Douglas Galasko, Serge Gauthier, and Gregory Jicha. 2007. 'Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria', The Lancet Neurology, 6: 734-46.
Esvald, Eli-Eelika, Jürgen Tuvikene, Alex Sirp, Sudarshan Patil, Clive R. Bramham, and Tõnis Timmusk. 2020. 'CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons', The Journal of Neuroscience, 40: 1405-26.
Fjell, Anders M, Linda McEvoy, Dominic Holland, Anders M Dale, Kristine B Walhovd, and Alzheimer's Disease Neuroimaging Initiative. 2014. 'What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus', Progress in neurobiology, 117: 20-40.
FLEMING, R., J. ZEISEL, and K. BENNETT. 2020. 'World Alzheimer Report 2020: Design Dignity Dementia: dementia-related design and the built environment ', Alzheimer’s Disease International. https://www.alzint.org/u/WorldAlzheimerReport2020Vol1.pdf.
Frisoni, Giovanni B, Nick C Fox, Clifford R Jack, Philip Scheltens, and Paul M Thompson. 2010. 'The clinical use of structural MRI in Alzheimer disease', Nature reviews neurology, 6: 67-77.
Fu, R., Q. Shen, P. Xu, J. J. Luo, and Y. Tang. 2014. 'Phagocytosis of microglia in the central nervous system diseases', Mol Neurobiol, 49: 1422-34.
Galvin, J. E. 2012. 'OPTIMIZING DIAGNOSIS AND MANANGEMENT IN MILD-TO-MODERATE ALZHEIMER'S DISEASE', Neurodegener Dis Manag, 2: 291-304.
Gibon, J., P. A. Barker, and P. Séguéla. 2016. 'Opposing presynaptic roles of BDNF and ProBDNF in the regulation of persistent activity in the entorhinal cortex', Mol Brain, 9: 23.
Ginsberg, Stephen D., Michael H. Malek-Ahmadi, Melissa J. Alldred, Yinghua Chen, Kewei Chen, Moses V. Chao, Scott E. Counts, and Elliott J. Mufson. 2019. 'Brain-derived neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary tangle pathology', Neurobiology of Disease, 132: 104540.
Goldmann, T., P. Wieghofer, M. J. Jordão, F. Prutek, N. Hagemeyer, K. Frenzel, L. Amann, O. Staszewski, K. Kierdorf, M. Krueger, G. Locatelli, H. Hochgerner, R. Zeiser, S. Epelman, F. Geissmann, J. Priller, F. M. Rossi, I. Bechmann, M. Kerschensteiner, S. Linnarsson, S. Jung, and M. Prinz. 2016. 'Origin, fate and dynamics of macrophages at central nervous system interfaces', Nat Immunol, 17: 797-805.
Gonzalez, A., G. Moya-Alvarado, C. Gonzalez-Billaut, and F. C. Bronfman. 2016. 'Cellular and molecular mechanisms regulating neuronal growth by brain-derived neurotrophic factor', Cytoskeleton (Hoboken), 73: 612-28.
Gouras, G. K., D. Tampellini, R. H. Takahashi, and E. Capetillo-Zarate. 2010. 'Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease', Acta Neuropathol, 119: 523-41.
Gray, S. C., K. J. Kinghorn, and N. S. Woodling. 2020. 'Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis', Neural Regen Res, 15: 1208-19.
Griciuc, Ana, and Rudolph E. Tanzi. 2021. 'The role of innate immune genes in Alzheimer's disease', Current Opinion in Neurology, 34: 228-36.
Guo, Tiantian, Denghong Zhang, Yuzhe Zeng, Timothy Y. Huang, Huaxi Xu, and Yingjun Zhao. 2020. 'Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease', Molecular Neurodegeneration, 15: 40.
Halliday, Glenda. 2017. 'Pathology and hippocampal atrophy in Alzheimer's disease', The Lancet Neurology, 16: 862-64.
Hansen, David V., Jesse E. Hanson, and Morgan Sheng. 2017. 'Microglia in Alzheimer’s disease', Journal of Cell Biology, 217: 459-72.
Heemels, Marie-Thérèse. 2016. 'Neurodegenerative diseases', Nature, 539: 179-79.
Hemonnot, Anne-Laure, Jennifer Hua, Lauriane Ulmann, and Hélène Hirbec. 2019. 'Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities', Frontiers in Aging Neuroscience, 11.
Hendrie, Hugh C. 1998. 'Epidemiology of dementia and Alzheimer's disease', The American Journal of Geriatric Psychiatry, 6: S3-S18.
Holtzman, David M., John C. Morris, and Alison M. Goate. 2011. 'Alzheimer's disease: the challenge of the second century', Science translational medicine, 3: 77sr1-77sr1.
Iqbal, K., F. Liu, C. X. Gong, and I. Grundke-Iqbal. 2010. 'Tau in Alzheimer disease and related tauopathies', Curr Alzheimer Res, 7: 656-64.
Iqbal, Khalid, Fei Liu, and Cheng-Xin Gong. 2016. 'Tau and neurodegenerative disease: the story so far', Nature reviews neurology, 12: 15.
Izumi, Daisuke, Shusuke Toden, Elsie Ureta, Takatsugu Ishimoto, Hideo Baba, and Ajay Goel. 2019. 'TIAM1 promotes chemoresistance and tumor invasiveness in colorectal cancer', Cell Death & Disease, 10: 267.
Je, H. S., F. Yang, Y. Ji, G. Nagappan, B. L. Hempstead, and B. Lu. 2012. 'Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses', Proc Natl Acad Sci U S A, 109: 15924-9.
Jeffery, Kate J. 2018. 'The hippocampus: from memory, to map, to memory map', Trends in neurosciences, 41: 64-66.
Jiang, B., L. Zhou, J. Lu, Y. Wang, C. Liu, W. Zhou, and J. Guo. 2021. 'Elevated TIAM2 expression promotes tumor progression and is associated with unfavorable prognosis in pancreatic cancer', Scand J Gastroenterol, 56: 59-67.
Josiane Budni, Tatiani Bellettini-Santos, Francielle Mina, Michelle Lima Garcez, Alexandra Ioppi Zugno. 2015. 'The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease', Aging and disease, 6: 331-41.
Kales, Helen C, Laura N Gitlin, and Constantine G Lyketsos. 2015. 'Assessment and management of behavioral and psychological symptoms of dementia', Bmj, 350.
Kalia, Madhu. 2003. 'Dysphagia and aspiration pneumonia in patients with Alzheimer’s disease', Metabolism, 52: 36-38.
Karantzoulis, S., and J. E. Galvin. 2011. 'Distinguishing Alzheimer's disease from other major forms of dementia', Expert Rev Neurother, 11: 1579-91.
Kellner, Y., N. Gödecke, T. Dierkes, N. Thieme, M. Zagrebelsky, and M. Korte. 2014. 'The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity', Front Synaptic Neurosci, 6: 5.
Kent, Sarah A., Tara L. Spires-Jones, and Claire S. Durrant. 2020. 'The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics', Acta Neuropathologica, 140: 417-47.
Kocahan, Sayad, and Zumrut Doğan. 2017. 'Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors', Clinical Psychopharmacology and Neuroscience, 15: 1-8.
Kwon, Munjin, José R. Fernández, Gregory F. Zegarek, Sean B. Lo, and Bonnie L. Firestein. 2011. 'BDNF-Promoted Increases in Proximal Dendrites Occur via CREB-Dependent Transcriptional Regulation of Cypin', The Journal of Neuroscience, 31: 9735-45.
Lane, C. A., J. Hardy, and J. M. Schott. 2018. 'Alzheimer's disease', European Journal of Neurology, 25: 59-70.
Lavanderos, Boris, Ian Silva, Pablo Cruz, Octavio Orellana-Serradell, María Paz Saldías, and Oscar Cerda. 2020. 'TRP Channels Regulation of Rho GTPases in Brain Context and Diseases', Frontiers in Cell and Developmental Biology, 8.
Leal, G., C. R. Bramham, and C. B. Duarte. 2017. 'BDNF and Hippocampal Synaptic Plasticity', Vitam Horm, 104: 153-95.
Leal, Graciano, Pedro M Afonso, Ivan L Salazar, and Carlos B Duarte. 2015. 'Regulation of hippocampal synaptic plasticity by BDNF', Brain research, 1621: 82-101.
Li, Huiwen, Xuelian Cui, Dingbao Chen, Yang Yang, Junjie Piao, Zhenhua Lin, Guanghai Yan, and Danhua Shen. 2016. 'Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma', Oncol Lett, 12: 3492-98.
Lin, Y. S., Y. F. Lin, K. C. Chen, Y. K. Yang, and Y. H. Hsiao. 2019. 'Collapsin response mediator protein 5 (CRMP5) causes social deficits and accelerates memory loss in an animal model of Alzheimer's disease', Neuropharmacology, 157: 107673.
Liu, Pei-Pei, Yi Xie, Xiao-Yan Meng, and Jian-Sheng Kang. 2019. 'History and progress of hypotheses and clinical trials for Alzheimer’s disease', Signal Transduction and Targeted Therapy, 4: 29.
Long, Justin M, and David M Holtzman. 2019. 'Alzheimer disease: an update on pathobiology and treatment strategies', Cell, 179: 312-39.
Lu, Bai, Guhan Nagappan, Xiaoming Guan, Pradeep J Nathan, and Paul Wren. 2013. 'BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases', Nature Reviews Neuroscience, 14: 401-16.
Lu, Bai, Petti T Pang, and Newton H Woo. 2005. 'The yin and yang of neurotrophin action', Nature Reviews Neuroscience, 6: 603-14.
Lu, Wei-Jen. 2019. 'TIAM2S exaggerates neuron-inflammation and neural damage through microglial priming', National Cheng Kung University.
Maclin, Joshua Marvin Anthony, Tao Wang, and Shifu Xiao. 2019. 'Biomarkers for the diagnosis of Alzheimer’s disease, dementia Lewy body, frontotemporal dementia and vascular dementia', General Psychiatry, 32: e100054.
Malek-Ahmadi, M., S. E. Perez, K. Chen, and E. J. Mufson. 2016. 'Neuritic and Diffuse Plaque Associations with Memory in Non-Cognitively Impaired Elderly', J Alzheimers Dis, 53: 1641-52.
Maltas, J., H. Reed, A. Porter, and A. Malliri. 2020. 'Mechanisms and consequences of dysregulation of the Tiam family of Rac activators in disease', Biochem Soc Trans, 48: 2703-19.
Manabe, T., Y. Fujikura, K. Mizukami, H. Akatsu, and K. Kudo. 2019. 'Pneumonia-associated death in patients with dementia: A systematic review and meta-analysis', PLoS One, 14: e0213825.
Matsuo, Naoki, Mikio Hoshino, Masato Yoshizawa, and Yo-ichi Nabeshima. 2002. 'Characterization of STEF, a Guanine Nucleotide Exchange Factor for Rac1, Required for Neurite Growth', The Journal of biological chemistry, 277: 2860-8.
McDonald, CR, LK McEvoy, L Gharapetian, C Fennema-Notestine, DJ Hagler, D Holland, A Koyama, JB Brewer, and AM Dale. 2009. 'Regional rates of neocortical atrophy from normal aging to early Alzheimer disease', Neurology, 73: 457-65.
McKhann, Guy M, David S Knopman, Howard Chertkow, Bradley T Hyman, Clifford R Jack Jr, Claudia H Kawas, William E Klunk, Walter J Koroshetz, Jennifer J Manly, and Richard Mayeux. 2011. 'The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging‐Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease', Alzheimer's & Dementia, 7: 263-69.
McQuade, A., and M. Blurton-Jones. 2019. 'Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk', J Mol Biol, 431: 1805-17.
Michalski, Bernadeta, Maria M Corrada, Claudia H Kawas, and Margaret Fahnestock. 2015. 'Brain-derived neurotrophic factor and TrkB expression in the “oldest-old,” the 90+ Study: correlation with cognitive status and levels of soluble amyloid-beta', Neurobiology of aging, 36: 3130-39.
Miller, Megan B., Yan Yan, Betty A. Eipper, and Richard E. Mains. 2013. 'Neuronal Rho GEFs in Synaptic Physiology and Behavior', The Neuroscientist, 19: 255-73.
Miranda, M., J. F. Morici, M. B. Zanoni, and P. Bekinschtein. 2019. 'Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain', Front Cell Neurosci, 13: 363.
Murphy, M. P., and H. LeVine, 3rd. 2010. 'Alzheimer's disease and the amyloid-beta peptide', J Alzheimers Dis, 19: 311-23.
Nagase, Miki, and Toshiro Fujita. 2013. 'Role of Rac1–mineralocorticoid-receptor signalling in renal and cardiac disease', Nature Reviews Nephrology, 9: 86-98.
Naito, Yusuke, Alfred Kihoon Lee, and Hideto Takahashi. 2017. 'Emerging roles of the neurotrophin receptor TrkC in synapse organization', Neuroscience research, 116: 10-17.
Nayak, D., T. L. Roth, and D. B. McGavern. 2014. 'Microglia development and function', Annu Rev Immunol, 32: 367-402.
Neumann, H., M. R. Kotter, and R. J. Franklin. 2009. 'Debris clearance by microglia: an essential link between degeneration and regeneration', Brain, 132: 288-95.
Norris, G. T., and J. Kipnis. 2019. 'Immune cells and CNS physiology: Microglia and beyond', J Exp Med, 216: 60-70.
Numakawa, Tadahiro, and Haruki Odaka. 2021. 'Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection', International Journal of Molecular Sciences, 22: 5719.
O'Brien, R. J., and P. C. Wong. 2011. 'Amyloid precursor protein processing and Alzheimer's disease', Annu Rev Neurosci, 34: 185-204.
Onuska, Kate M. 2020. 'The Dual Role of Microglia in the Progression of Alzheimer's Disease', The Journal of Neuroscience, 40: 1608-10.
Petrella, Carla, Maria G Di Certo, Christian Barbato, Francesca Gabanella, Massimo Ralli, Antonio Greco, Roberta Possenti, and Cinzia Severini. 2019. 'Neuropeptides in Alzheimer’s Disease: An Update', Current Alzheimer Research, 16: 544-58.
Pini, L., M. Pievani, M. Bocchetta, D. Altomare, P. Bosco, E. Cavedo, S. Galluzzi, M. Marizzoni, and G. B. Frisoni. 2016. 'Brain atrophy in Alzheimer's Disease and aging', Ageing Res Rev, 30: 25-48.
Razani, J., R. Corona, J. Quilici, A. A. Matevosyan, C. Funes, A. Larco, B. Miloyan, J. Avila, J. Chung, H. Goldberg, and P. Lu. 2014. 'The Effects of Declining Functional Abilities in Dementia Patients and Increases Psychological Distress on Caregiver Burden Over a One-Year Period', Clin Gerontol, 37: 235-52.
Reisberg, Barry, SH Ferris, MJ De Leon, A Kluger, E Franssen, J Borenstein, and RC Alba. 1989. 'The stage specific temporal course of Alzheimer's disease: functional and behavioral concomitants based upon cross-sectional and longitudinal observation', Progress in clinical and biological research, 317: 23-41.
Rosas-Vidal, Luis E, Fabricio H Do-Monte, Francisco Sotres-Bayon, and Gregory J Quirk. 2014. 'Hippocampal–prefrontal BDNF and memory for fear extinction', Neuropsychopharmacology, 39: 2161-69.
Saitgareeva, Aigul R., Kirill V. Bulygin, Ilgiz F. Gareev, Ozal A. Beylerli, and Leila R. Akhmadeeva. 2020. 'The role of microglia in the development of neurodegeneration', Neurological Sciences, 41: 3609-15.
Sasi, Manju, Beatrice Vignoli, Marco Canossa, and Robert Blum. 2017. 'Neurobiology of local and intercellular BDNF signaling', Pflügers Archiv-European Journal of Physiology, 469: 593-610.
Scott, Kevin R, and Anna M Barrett. 2007. 'Dementia syndromes: evaluation and treatment', Expert review of neurotherapeutics, 7: 407-22.
Serrano-Pozo, A., M. P. Frosch, E. Masliah, and B. T. Hyman. 2011. 'Neuropathological alterations in Alzheimer disease', Cold Spring Harb Perspect Med, 1: a006189.
Shirazi Fard, S., J. Kele, M. Vilar, G. Paratcha, and F. Ledda. 2010. 'Tiam1 as a signaling mediator of nerve growth factor-dependent neurite outgrowth', PLoS One, 5: e9647.
Stalder, M., A. Phinney, A. Probst, B. Sommer, M. Staufenbiel, and M. Jucker. 1999. 'Association of microglia with amyloid plaques in brains of APP23 transgenic mice', Am J Pathol, 154: 1673-84.
Taiwan National Development Council Executive Yuan, . 2018. 'Population Projections for R.O.C (Taiwan): 2018-2065', Taiwan, National Development Council, Executive Yuan. https://www.ndc.gov.tw/en/cp.aspx?n=2E5DCB04C64512CC.
Takai, Y., T. Sasaki, and T. Matozaki. 2001. 'Small GTP-binding proteins', Physiol Rev, 81: 153-208.
Tarawneh, R., and D. M. Holtzman. 2012. 'The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment', Cold Spring Harb Perspect Med, 2: a006148.
Terawaki, Shin‐ichi, Ken Kitano, Tomoyuki Mori, Yan Zhai, Yoshiki Higuchi, Norimichi Itoh, Takashi Watanabe, Kozo Kaibuchi, and Toshio Hakoshima. 2010. 'The PHCCEx domain of Tiam1/2 is a novel protein‐and membrane‐binding module', The EMBO journal, 29: 236-50.
Torres, Diana Marcela Cuestas, and Fernando P. Cardenas. 2020. 'Synaptic plasticity in Alzheimer’s disease and healthy aging', Reviews in the Neurosciences, 31: 245-68.
United Nations, . 2020. 'World Population Ageing 2020 Highlights: Living Arrangements of Older Persons', United Nations. https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/files/documents/2020/Sep/un_pop_2020_pf_ageing_10_key_messages.pdf.
Vilar, Marçal, and Helena Mira. 2016. 'Regulation of neurogenesis by neurotrophins during adulthood: expected and unexpected roles', Frontiers in Neuroscience, 10: 26.
Volosin, Marta, Wenyu Song, Ramiro D Almeida, David R Kaplan, Barbara L Hempstead, and Wilma J Friedman. 2006. 'Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins', Journal of Neuroscience, 26: 7756-66.
Wang, Liang, Xingya Chang, Liang She, Duo Xu, Wei Huang, and Mu-ming Poo. 2015. 'Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons', Journal of Neuroscience, 35: 8384-93.
Wattmo, C., A. K. Wallin, and L. Minthon. 2013. 'Progression of mild Alzheimer's disease: knowledge and prediction models required for future treatment strategies', Alzheimers Res Ther, 5: 44.
West, AE, P Pruunsild, and T Timmusk. 2014. 'Neurotrophins: transcription and translation', Neurotrophic factors: 67-100.
Woroniuk, Anna, Andrew Porter, Gavin White, Daniel T. Newman, Zoi Diamantopoulou, Thomas Waring, Claire Rooney, Douglas Strathdee, Daniel J. Marston, Klaus M. Hahn, Owen J. Sansom, Tobias Zech, and Angeliki Malliri. 2018. 'STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap', Nature Communications, 9: 2124.
Xiong, Huangui. 2008. 'Hippocampus and Spatial Memory.' in Howard E. Gendelman and Tsuneya Ikezu (eds.), Neuroimmune Pharmacology (Springer US: Boston, MA).
Yen, Wei-Hsuan, Wu-Sian Ke, Jan-Jong Hung, Tsung-Ming Chen, Jia-Shing Chen, and H. S. Sun. 2016. 'Sp1-mediated ectopic expression of T-cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma', Cancer Medicine, 5: 465-77.
Yin, J., K. L. Valin, M. L. Dixon, and J. W. Leavenworth. 2017. 'The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer', J Immunol Res, 2017: 5150678.
Yoo, S., Y. Kim, H. Lee, S. Park, and S. Park. 2012. 'A gene trap knockout of the Tiam-1 protein results in malformation of the early embryonic brain', Mol Cells, 34: 103-8.
Zheng, Yi. 2001. 'Dbl family guanine nucleotide exchange factors', Trends in biochemical sciences, 26: 724-32.