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研究生：	廖翊均 Liao, Yi-Chun
論文名稱：	探討人類 TIAM2S 在老化空間記憶喪失中所扮演的角色及其分子機制 Investigation of the roles and mechanisms of human TIAM2S in spatial memory impairment during aging
指導教授：	朱俊憲 Chu, Chun-Hsien
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2022
畢業學年度：	110
語文別：	英文
論文頁數：	41
中文關鍵詞：	TIAM2S 蛋白、晚發性阿茲海默症、空間記憶受損、海馬迴、內側前額葉皮層、γ-胺基丁酸
外文關鍵詞：	TIAM2S, LOAD, spatial memory impairment, hippocampus, mPFC, GABA
相關次數：	點閱：111 下載：7
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晚發性阿茲海默症(LOAD)是一種和年紀相關、進行性的神經退化性疾病，伴隨著認知、行為和具有功能的能力受損，特別是在空間記憶喪失方面。然而，基因遺傳對LOAD 發病機制的影響目前仍不清楚。流行病學遺傳學與基因體資料分析研究報告稱，人類 TIAM2 (human TIAM Rac1 associated GEF 2; TIAM2S)基因的基因組變異與LOAD 的發病風險和致病性顯著相關。在正常、非腫瘤的情況下，TIAM2S 蛋白，而不是 TIAM2L 蛋白，在大腦中是可以被檢測到的。此外，我們的初步數據顯示，AD 患者的海馬迴中的 TIAM2S 蛋白表現量增加。因此，我們假設 TIAM2S 可能影響與年齡相關的空間記憶喪失，並參與在晚發性阿茲海默症的致病性中。在目前的研究中，過度表現人類 TIAM2S 的基因轉殖鼠(TIAM2S-TG mice)被用來探討人類 TIAM2S 在老化過程中，在 AD 神經病理學標誌和空間記憶障礙發展中所扮演的角色及其機制。首先，在不同年齡（12 個月和 18 個月大）和性別（公和母）的 WT 和 TIAM2S-TG小鼠進行物體辨識測驗(Object location task)和水迷宮測驗(The Morris water maze test)。物體辨識測驗的 DI 值(discrimination index; DI) 結果分析表明，老年的公 WT 小鼠 DI值為正，表明有更多時間調查新位置的物體。這些數據暗示 WT 小鼠在中老年時具有正常的空間記憶。然而，TIAM2S-TG 小鼠在老年而非中年時的 DI 值為零或負值，表明 18 個月大的公 TIAM2S-TG 小鼠無法識別物體被重新定位。同樣的，水迷宮測驗表明，與老年的公 WT 小鼠相較，18 個月大的公 TIAM2S-TG 小鼠在 2 分鐘的訓練時間內無法找到平台；並且在第五天測試，當天在目標象限區域花費的時間較少。總之，這些數據表明 TIAM2S-TG 小鼠可以發展與年齡相關的空間記憶障礙。其次，利用免疫螢光染色(Immunofluorescence staining; IF staining)進行過磷酸化的 tau 蛋白［phosphorylated-Tau (Ser369)］、Oligomers (A11)、澱粉樣蛋白斑塊(Amyloid β; Aβ)、和 Iba-1 的染色，以及西方墨點法(Western blot)分析 NeuN 和 IL-1β 的蛋白表現量以進一步確定老年公 WT 和 TIAM2S-TG 小鼠的海馬迴區域中的原發性病理性 AD標誌。我們的數據顯示，老年的 WT 和 TIAM2S-TG 小鼠海馬迴中的 NeuN 和 Iba1 表現相似。然而，在老年的 TIAM2S-TG 小鼠 DG/CA1 區域中的 p-Tau (Ser369) 和Aβ的表達顯著增加。接下來，通過結合T2-weighted images、化學交換飽和轉移（CEST）和擴散張量影像(Diffusion Tensor Imaging; DTI)等多個核磁共振成像(Magnetic resonance imaging; MRI)，我們想確定人類 TIAM2S 的早期病理機制介導的與年齡相關的空間記憶障礙。我們的分析結果顯示中年的公 TIAM2S-TG 小鼠的海馬體增大，同時 GABA 這個抑制性神經傳遞物質比公WT 小鼠來的高。此外，人類 TIAM2S 過表達引起的海馬迴連接變化及其與 mPFC 的相互作用可能導致 TIAM2S-TG 小鼠在老年時出現空間記憶障礙。總結就是，這項研究不僅拓寬了我們對晚發性阿茲海默症的發病機制的基本認識，而且確定了 TIAM2S 在與年齡相關的空間記憶障礙發展中的促進作用。

Late-onset Alzheimer's disease (LOAD) is an age-related, progressive, degenerative brain disease along with the impairment of cognitive, behavioral, and functional abilities, especially the spatial memory loss. However, the mechanisms underlying in the genetic influence on the progression of LOAD pathogenesis remains unclear. In this regard, the epidemiological genetic studies reported that the genomic variants of human TIAM Rac1 accompanied with GEF 2 (TIAM2) gene were significantly associated with the risk and pathogenesis of LOAD. Generally, it is clear that in the non-neoplastic conditions, the human short-form TIAM2 (TIAM2S) protein, but not the long form, is abundant and detectable in the brains. In addition, our preliminary reports revealed that TIAM2S protein was increased in the hippocampus of AD patients. Therefore, we hypothesized that TIAM2S might affect the age-related spatial memory impairment and involve in LOAD pathogenesis. In the current study, the transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) was used to determine the possible roles of human TIAM2S in the development of the spatial memory impairment during aging and to propose its early pathological mechanisms. First, the multiple animal behavioral tests including the object location task and the water maze test were performed in the WT and TIAM2S-TG mice with different ages (12 and 18 months old) and the genders (male and female). The results from the object location task revealed that the WT mice could maintain their discrimination index (DI) as a positive value during aging, indicating the longer time investigation for locating the new object. These data implied that the WT mice had the normal spatial memory in the middle and old ages. However, the zero or negative DI value of the TIAM2S-TG mice in the old age, but not in the middle age, indicated that the 18-month-old male TIAM2S-TG mice failed to recognize when an object was relocated. Consistently, the water maze test showed that the 18-monthold male WT mice displayed the normal spatial and learning memory, but the aged-match TIAM2S-TG mice could not search the platform in a 2-minute training time and spent less time in the region of the target quadrant at the day of testing. These data combined together suggested that the TIAM2S-TG mice could develop the age-related spatial memory impairment. Additionally, the immunofluorescence (IF) staining for phosphorylated-Tau (Ser369), Oligomers (A11), Aβ, and Iba-1 expression and western blots for NeuN and IL-1β level were performed in order to further determine the primary pathological AD hallmarks in the hippocampal regions of the old male WT and TIAM2S-TG mice. The data of this study showed that the levels of hippocampal NeuN and Iba-1 in the old WT and TIAM2S-TG mice were similar. However, expression of p-Tau (Ser369) and Aβ was found to be increased significantly in the DG/CA1 region of old TIAM2S-TG mice. Further, by combining the multiple magnetic resonance imaging sequences including T2-weighted images, diffusion weight imaging (DWI), chemical exchange saturation transfer (CEST), and diffusion tensor images (DTI), we determined the early pathological mechanisms of human TIAM2Smediated age-related spatial memory impairment. The results revealed that the middle-aged male TIAM2S-TG mice have enlarged hippocampus along with high GABA inhibitory neurotransmitter than that of the WT male. Moreover, it was suggested that the alternation of hippocampal connectivity and its interaction with mPFC by human TIAM2S overexpression might cause the development of spatial memory impairment in the case of TIAM2S-TG mice in the old age. Thus, it was concluded that, this study did not only broaden the fundamental understanding of LOAD pathogenesis but also identified the promoting role of TIAM2S in the development of an age-related spatial memory.

摘要   I
Abstract   II
誌謝   III
List of figures   VI
Introduction   1
   1. TIAM subfamily   1
         1.1 Protein domains in human TIAM1 and TIAM2   1
         1.2 TIAM Rac1 associated GEF 1 (TIAM1)   1
         1.3 Mouse TIAM Rac1 Associated GEF 2 (TIAM2/Stef)   2
         1.4 Human TIAM Rac1 Associated GEF 2 (TIAM2)    2
  2. Spatial memory and the neuron circuits   3
         2.1 Hippocampus   3
         2.2 Medial prefrontal cortex (mPFC)    4
  3. Alzheimer’s disease (AD)    5
         3.1 Pathological hallmarks of Alzheimer’s disease    5
         3.2 Early-onset/Familial Alzheimer’s disease (EOAD/FAD)    6
         3.3 Late-onset/Sporadic Alzheimer’s disease (LOAD/SAD)   6
  4. Applications of T2- weighted, chemical exchange saturation transfer, diffusion 
      magnetic resonance imaging (dMRI), and diffusion weighted imaging (DWI) for 
      brain structure, neurotransmitters, neural fiber density and microenvironments 
      6
  5. Objective of this study     7

Materials and methods     9
  1. Animals               9
  2. Animal behavior tests             9
        2.1 The Morris water maze        9
        2.2 Object location task             9
        2.3 Y maze                                    9
  3. Brain cryostat section     10
  4. Immunofluorescence staining     10
  5. Western blot             10
  6. Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) examination 
and chemical Exchange Saturation Transfer (CEST) Imaging             11
  7. Antibody                11
  8. Statistical analysis    11

Results           12
  1. Development of age-related spatial memory deficits in TIAM2S transgenic mice 
      12
  2. Primary AD pathological hallmarks in the hippocampus of old TIAM2S-TG mice
      13
  3. Edema free abnormally enlarged hippocampus in the middle-aged male 
      TIAM2STG mice     14
  4. Alternation of the hippocampal fibers and mPFC-hippocampus paths along 
      with the higher inhibitory neurotransmitter GABA in the middle-aged male 
      TIAM2S-TG mice    14

Discussion          16
The assessments of the animal spatial memory tests      16
Microglia activation and pathological AD hallmarks in old TIAM2S-TG mice     16
Early pathological mechanism of age-related spatial memory impairment: mPFC-
hippocampus paths and inhibitory neurotransmitter GABA           17

Conclusion        18
Figures                19
Figure 1. Male TIAM2S-TG mice display age-related spatial memory deficits       20
Figure 2. Aged male TIAMS2-TG mice have increased Tau phosphorylation and Aβ in their DG/CA1 brain regions      24
Figure 3. Expression of hippocampal NeuN protein in aged male WT and TIAM2S-TG mice      25
Figure 4. Male TIAMS2-TG mice have enlarged hippocampal size without edema 27
Figure 5. Male TIAMS2-TG mice have higher level of inhibitory neurotransmitter 
GABA in hippocampus                   29
Figure 6. Male TIAMS2-TG mice have increased in fiber number of hippocampus but decreased in mPFC-hippocampus paths             31

Supplements       32
Supplementary Figure 1. Female TIAM2S-TG mice display spatial memory deficits in middle age    32
Supplementary Figure 2. Y maze of WT and TIAM2S-TG mice in the middle and old 
ages                       33
Supplementary Figure 3. Expression of Iba-1 and IL-1β in male TIAM2S-TG and WT 
mice in old age          35

Reference       36
                                    

Aamodt, E. J., & Williams Jr, R. C. (1984). Microtubule-associated proteins connect microtubules and neurofilaments in vitro. Biochemistry, 23(25), 6023-6031.
Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., . . . Fiebich, B. L. (2000). Inflammation and Alzheimer’s disease. Neurobiology of aging, 21(3), 383-421.
Alonso, A. d. C., Grundke-Iqbal, I., Barra, H. S., & Iqbal, K. (1997). Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proceedings of the national academy of sciences, 94(1), 298-303.
Anderson, J. R. (2013). Language, memory, and thought: Psychology Press.
Bartos, M., Vida, I., Frotscher, M., Meyer, A., Monyer, H., Geiger, J. R., & Jonas, P. (2002). Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proceedings of the national academy of sciences, 99(20), 13222-13227.
Bisht, K., Sharma, K. P., Lecours, C., Gabriela Sánchez, M., El Hajj, H., Milior, G., . . . Vallieres, L. (2016). Dark microglia: a new phenotype predominantly associated with pathological states. Glia, 64(5), 826-839.
Blennow, K. (2006). de leon, MJ, Zetterberg, H. Lancet, 368, 387-403.
Bowley, M. P., Drevets, W. C., Öngür, D., & Price, J. L. (2002). Low glial numbers in the amygdala in major depressive disorder. Biological psychiatry, 52(5), 404-412.
Braak, H., & Braak, E. (1990). Morphology of Alzheimer disease. Fortschritte der Medizin, 108(33), 621-624.
Brandler, W. M., Antaki, D., Gujral, M., Noor, A., Rosanio, G., Chapman, T. R., . . . Watts, A. C. (2016). Frequency and complexity of de novo structural mutation in autism. The American Journal of Human Genetics, 98(4), 667-679.
Bydder, G. M. (2010). Imaging of short and ultrashort T2 and T2* tissues using clinical MRI systems. Imaging in Medicine, 2(2), 225.
Cai, K., Haris, M., Singh, A., Kogan, F., Greenberg, J. H., Hariharan, H., . . . Reddy, R. (2012). Magnetic resonance imaging of glutamate. Nature medicine, 18(2), 302-306.
Chan, Y.-L., Lai, W.-C., Chen, J.-S., Tseng, J. T.-C., Chuang, P.-C., Jou, J., . . . Sun, H. S. (2020). TIAM2S mediates serotonin homeostasis and provokes a pro-inflammatory immune microenvironment permissive for colorectal tumorigenesis. Cancers, 12(7), 1844.
Chen, G.-f., Xu, T.-h., Yan, Y., Zhou, Y.-r., Jiang, Y., Melcher, K., & Xu, H. E. (2017). Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacologica Sinica, 38(9), 1205-1235.
Chen, J. S., Su, I. J., Leu, Y. W., Young, K. C., & Sun, H. S. (2012). Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer. Int J Cancer, 130(6), 1302-1313. doi:10.1002/ijc.26117
Cheng, J., Scala, F., Blanco, F. A., Niu, S., Firozi, K., Keehan, L., . . . Duman, J. G. (2021). The Rac-GEF Tiam1 promotes dendrite and synapse stabilization of dentate granule cells and restricts hippocampal-dependent memory functions. Journal of Neuroscience, 41(6), 1191-1206.
Chiu, C.-Y., Leng, S., Martin, K. A., Kim, E., Gorman, S., & Duhl, D. M. (1999). Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1. Genomics, 61(1), 66-73.
Chu, C. H., Chen, J. S., Chuang, P. C., Su, C. H., Chan, Y. L., Yang, Y. J., . . . Sun, H. S. (2020). TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior. FASEB J, 34(2), 3267-3288. doi:10.1096/fj.201901323R
Coughlan, G., Laczó, J., Hort, J., Minihane, A.-M., & Hornberger, M. (2018). Spatial navigation deficits—overlooked cognitive marker for preclinical Alzheimer disease? Nature Reviews Neurology, 14(8), 496-506.
D’Hooge, R., & De Deyn, P. P. (2001). Applications of the Morris water maze in the study of learning and memory. Brain research reviews, 36(1), 60-90.
Davies, D. S., Ma, J., Jegathees, T., & Goldsbury, C. (2017). Microglia show altered morphology and reduced arborization in human brain during aging and A lzheimer's disease. Brain Pathology, 27(6), 795-808.
Di Fede, G., Catania, M., Morbin, M., Rossi, G., Suardi, S., Mazzoleni, G., . . . Erbetta, A. (2009). A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science, 323(5920), 1473-1477.
Dietrich, O., Biffar, A., Baur-Melnyk, A., & Reiser, M. F. (2010). Technical aspects of MR diffusion imaging of the body. European journal of radiology, 76(3), 314-322.
Eichenbaum, H. (2017). Prefrontal-hippocampal interactions in episodic memory. Nat Rev Neurosci, 18(9), 547-558. doi:10.1038/nrn.2017.74
Eichenbaum, H. (2017). Prefrontal–hippocampal interactions in episodic memory. Nature Reviews Neuroscience, 18(9), 547-558.
Ertekin-Taner, N. (2007). Genetics of Alzheimer's disease: a centennial review. Neurologic clinics, 25(3), 611-667.
Euston, D. R., Gruber, A. J., & McNaughton, B. L. (2012). The role of medial prefrontal cortex in memory and decision making. Neuron, 76(6), 1057-1070. doi:10.1016/j.neuron.2012.12.002
Faingold, C. L., Gehlbach, G., & Caspary, D. M. (1989). On the role of GABA as an inhibitory neurotransmitter in inferior colliculus neurons: iontophoretic studies. Brain research, 500(1-2), 302-312.
Giulian, D. (1999). Microglia and the immune pathology of Alzheimer disease. Am J Hum Genet, 65(1), 13-18. doi:10.1086/302477
Goto, A., Hoshino, M., Matsuda, M., & Nakamura, T. (2011). Phosphorylation of STEF/Tiam2 by protein kinase A is critical for Rac1 activation and neurite outgrowth in dibutyryl cAMP–treated PC12D cells. Molecular biology of the cell, 22(10), 1780-1790.
Hölscher, C. (1999). Stress impairs performance in spatial water maze learning tasks. Behavioural brain research, 100(1-2), 225-235.
Habets, G., Van der Kammen, R., Jenkins, N. A., Gilbert, D., Copeland, N. G., Hagemeijer, A., & Collard, J. G. (1995). The invasion-inducing TIAM1 gene maps to human chromosome band 21q22 and mouse chromosome 16. Cytogenetic and Genome Research, 70(1-2), 48-51.
Habets, G. G., Scholtes, E. H., Zuydgeest, D., van der Kammen, R. A., Stam, J. C., Berns, A., & Collard, J. G. (1994). Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell, 77(4), 537-549.
Hainmueller, T., & Bartos, M. (2020). Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories. Nature Reviews Neuroscience, 21(3), 153-168.
Hanisch, U. K., & Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci, 10(11), 1387-1394. doi:10.1038/nn1997
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer disease. Nature Reviews Neuroscience, 16(6), 358-372.
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008). Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. Journal of Neuroscience, 28(33), 8354-8360.
Hoover, W. B., & Vertes, R. P. (2007). Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Structure and Function, 212(2), 149-179.
Hoshino, M., Sone, M., Fukata, M., Kuroda, S., Kaibuchi, K., Nabeshima, Y.-i., & Hama, C. (1999). Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1. Journal of Biological Chemistry, 274(25), 17837-17844.
Jay, T. M., Glowinski, J., & Thierry, A.-M. (1989). Selectivity of the hippocampal projection to the prelimbic area of the prefrontal cortex in the rat. Brain research, 505(2), 337-340.
Jay, T. M., & Witter, M. P. (1991). Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris‐leucoagglutinin. Journal of Comparative Neurology, 313(4), 574-586.
Jiménez-Balado, J., & Eich, T. S. (2021). GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease. Paper presented at the Seminars in cell & developmental biology.
Jin, J., & Maren, S. (2015). Prefrontal-Hippocampal Interactions in Memory and Emotion. Front Syst Neurosci, 9, 170. doi:10.3389/fnsys.2015.00170
Kangarlu, A., Parsey, R. V., & Bourekas, E. C. (2012). MRI in Neurosciences. In (Vol. 2012): Hindawi.
Kesner, R. P., & Novak, J. M. (1982). Serial position curve in rats: Role of the dorsal hippocampus. Science, 218(4568), 173-175.
Kier, E. L., Kim, J. H., Fulbright, R. K., & Bronen, R. A. (1997). Embryology of the human fetal hippocampus: MR imaging, anatomy, and histology. American journal of neuroradiology, 18(3), 525-532.
Kim, S. C., Song, K. B., Jung, Y. S., Kim, Y. H., Park, D. H., Lee, S. S., . . . Park, K. M. (2013). Short-term clinical outcomes for 100 consecutive cases of laparoscopic pylorus-preserving pancreatoduodenectomy: improvement with surgical experience. Surgical endoscopy, 27(1), 95-103.
Kolb, B., & Whishaw, I. Q. (2009). Fundamentals of human neuropsychology: Macmillan.
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., . . . Heppner, F. L. (2013). Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PloS one, 8(4), e60921.
Kraeuter, A.-K., Guest, P. C., & Sarnyai, Z. (2019). The Y-maze for assessment of spatial working and reference memory in mice. In Pre-clinical models (pp. 105-111): Springer.
Lee, H.-J., & Zheng, J. J. (2010). PDZ domains and their binding partners: structure, specificity, and modification. Cell communication and Signaling, 8(1), 1-18.
Leeuwen, F. N. v., Kain, H. E., Kammen, R. A. v. d., Michiels, F., Kranenburg, O. W., & Collard, J. G. (1997). The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. The Journal of cell biology, 139(3), 797-807.
Leng, F., & Edison, P. (2021). Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nature Reviews Neurology, 17(3), 157-172.
Levenga, J., Krishnamurthy, P., Rajamohamedsait, H., Wong, H., Franke, T. F., Cain, P., . . . Hoeffer, C. A. (2013). Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. Acta neuropathologica communications, 1(1), 1-14.
Lewejohann, L., Skryabin, B., Sachser, N., Prehn, C., Heiduschka, P., Thanos, S., . . . Pleskacheva, M. (2004). Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behavioural brain research, 154(1), 273-289.
Lipp, H.-P., & Wolfer, D. P. (1998). Genetically modified mice and cognition. Current opinion in neurobiology, 8(2), 272-280.
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019). History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal transduction and targeted therapy, 4(1), 1-22.
Ma, J., Brewer Jr, H. B., & Potter, H. (1996). Alzheimer Aβ neurotoxicity: promotion by antichymotrypsin, apoE4; inhibition by Aβ-related peptides. Neurobiology of aging, 17(5), 773-780.
McCormick, D. A. (1989). GABA as an inhibitory neurotransmitter in human cerebral cortex. Journal of neurophysiology, 62(5), 1018-1027.
Meda, S. A., Koran, M. E. I., Pryweller, J. R., Vega, J. N., Thornton-Wells, T. A., & Initiative, A. s. D. N. (2013). Genetic interactions associated with 12-month atrophy in hippocampus and entorhinal cortex in Alzheimer's Disease Neuroimaging Initiative. Neurobiology of aging, 34(5), 1518. e1519-1518. e1518.
Mertens, A. E., Roovers, R. C., & Collard, J. G. (2003). Regulation of Tiam1–rac signalling. FEBS letters, 546(1), 11-16.
Michiels, F., Habets, G. G., Stam, J. C., van der Kammen, R. A., & Collard, J. G. (1995). A role for Rac in Tiaml-induced membrane ruffling and invasion. Nature, 375(6529), 338-340.
Miller, J. F., Neufang, M., Solway, A., Brandt, A., Trippel, M., Mader, I., . . . Jacobs, J. (2013). Neural activity in human hippocampal formation reveals the spatial context of retrieved memories. Science, 342(6162), 1111-1114.
Mishra, A., Kim, H. J., Shin, A. H., & Thayer, S. A. (2012). Synapse loss induced by interleukin-1β requires pre-and post-synaptic mechanisms. Journal of Neuroimmune Pharmacology, 7(3), 571-578.
Molenaar, J. J., Koster, J., Zwijnenburg, D. A., Van Sluis, P., Valentijn, L. J., Van Der Ploeg, I., . . . Van Arkel, J. (2012). Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature, 483(7391), 589-593.
Morgan, J. T., Nordahl, C. W., & Schumann, C. M. (2012). The amygdala in autism spectrum disorders. The neuroscience of autism spectrum disorders. Amsterdam: Elseveier, 297-312.
Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B., & Lannfelt, L. (1992). A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid. Nature genetics, 1(5), 345-347.
Najm, R., Jones, E. A., & Huang, Y. (2019). Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Molecular neurodegeneration, 14(1), 1-13.
Niikura, T., Tajima, H., & Kita, Y. (2006). Neuronal cell death in Alzheimer's disease and a neuroprotective factor, humanin. Current neuropharmacology, 4(2), 139-147.
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308(5726), 1314-1318.
Rabinovici, G. D. (2019). Late-onset Alzheimer disease. Continuum: Lifelong Learning in Neurology, 25(1), 14.
Ramos, B., Baglietto-Vargas, D., del Rio, J. C., Moreno-Gonzalez, I., Santa-Maria, C., Jimenez, S., . . . Ruano, D. (2006). Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1× APP transgenic model of Alzheimer's disease. Neurobiology of aging, 27(11), 1658-1672.
Rechsteiner, M. (1990). PEST sequences are signals for rapid intracellular proteolysis. Paper presented at the Seminars in cell biology.
Reitz, C., & Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical pharmacology, 88(4), 640-651.
Rooney, C., White, G., Nazgiewicz, A., Woodcock, S. A., Anderson, K. I., Ballestrem, C., & Malliri, A. (2010). The Rac activator STEF (Tiam2) regulates cell migration by microtubule‐mediated focal adhesion disassembly. EMBO reports, 11(4), 292-298.
Sahai, E., & Marshall, C. J. (2002). RHO–GTPases and cancer. Nature Reviews Cancer, 2(2), 133-142.
Sasaki, N., Kurisu, J., & Kengaku, M. (2010). Sonic hedgehog signaling regulates actin cytoskeleton via Tiam1–Rac1 cascade during spine formation. Molecular and Cellular Neuroscience, 45(4), 335-344.
Sauer, J.-F., & Bartos, M. (2020). The role of the dentate gyrus in mnemonic functions. Neuroforum, 26(4), 247-254.
Schultz, C., & Engelhardt, M. (2014). Anatomy of the hippocampal formation. The Hippocampus in Clinical Neuroscience, 34, 6-17.
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011). Neuropathological alterations in Alzheimer disease. Cold Spring Harbor perspectives in medicine, 1(1), a006189.
Sharma, S., Rakoczy, S., & Brown-Borg, H. (2010). Assessment of spatial memory in mice. Life sciences, 87(17-18), 521-536.
Sisodia, S., Koo, E., Beyreuther, K., Unterbeck, A., & Price, D. (1990). Evidence that β-amyloid protein in Alzheimer's disease is not derived by normal processing. Science, 248(4954), 492-495.
Song, W. M., & Colonna, M. (2018). The identity and function of microglia in neurodegeneration. Nat Immunol, 19(10), 1048-1058. doi:10.1038/s41590-018-0212-1
Spittau, B. (2017). Aging microglia—phenotypes, functions and implications for age-related neurodegenerative diseases. Frontiers in aging neuroscience, 9, 194.
Squire, L. R., & Zola, S. M. (1996). Structure and function of declarative and nondeclarative memory systems. Proceedings of the national academy of sciences, 93(24), 13515-13522.
Tolar, M., Abushakra, S., & Sabbagh, M. (2020). The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimers Dement, 16(11), 1553-1560. doi:10.1016/j.jalz.2019.09.075
Tsai, S.-Y. (2013). Impact of a breastfeeding-friendly workplace on an employed mother's intention to continue breastfeeding after returning to work. Breastfeeding Medicine, 8(2), 210-216.
VanGuilder, H. D., Bixler, G. V., Brucklacher, R. M., Farley, J. A., Yan, H., Warrington, J. P., . . . Freeman, W. M. (2011). Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. Journal of neuroinflammation, 8(1), 1-21.
Wegmann, S., Eftekharzadeh, B., Tepper, K., Zoltowska, K. M., Bennett, R. E., Dujardin, S., . . . Commins, C. (2018). Tau protein liquid–liquid phase separation can initiate tau aggregation. The EMBO journal, 37(7), e98049.
Whitwell, J. L., Jack Jr, C. R., Przybelski, S. A., Parisi, J. E., Senjem, M. L., Boeve, B. F., . . . Josephs, K. A. (2011). Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis. Neurobiology of aging, 32(9), 1531-1541.
Wiley, J. (2021). Alzheimer’s disease facts and figures. Alzheimers Dement, 17, 327-406.
Wu, B., Warnock, G., Zaiss, M., Lin, C., Chen, M., Zhou, Z., . . . Delso, G. (2016). An overview of CEST MRI for non-MR physicists. EJNMMI physics, 3(1), 1-21.
Yankner, B. A., Duffy, L. K., & Kirschner, D. A. (1990). Neurotrophic and neurotoxic effects of amyloid β protein: reversal by tachykinin neuropeptides. Science, 250(4978), 279-282.
Yen, W. H., Ke, W. S., Hung, J. J., Chen, T. M., Chen, J. S., & Sun, H. (2016). Sp1‐mediated ectopic expression of T‐cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma. Cancer medicine, 5(3), 465-477.
Zaldua, N., Gastineau, M., Hoshino, M., Lezoualc’h, F., & Zugaza, J. L. (2007). Epac signaling pathway involves STEF, a guanine nucleotide exchange factor for Rac, to regulate APP processing. FEBS letters, 581(30), 5814-5818.
Zhao, Z.-Y., Han, C.-G., Liu, J.-T., Wang, C.-L., Wang, Y., & Cheng, L.-Y. (2013). TIAM2 enhances non-small cell lung cancer cell invasion and motility. Asian Pacific Journal of Cancer Prevention, 14(11), 6305-6309.

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