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Aging and disease    2020, Vol. 11 Issue (6) : 1423-1443     DOI: 10.14336/AD.2020.0201
Orginal Article |
Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice
Xingzhi Guo1, Yanying Liu1, David Morgan2, Li-Ru Zhao1,*
1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, 13210, USA
2Translational Neuroscience, Michigan State University, College of Human Medicine, Grand Rapids, Michigan, 49503, USA
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Abstract  

Alzheimer’s disease (AD), characterized by the accumulation of β-amyloid (Aβ) plaques and tau neurofibrillary tangles in the brain, neuroinflammation and neurodegeneration, is the most common form of neurodegenerative disease among the elderly. No effective treatment is available now in restricting the pathological progression of AD. The aim of this study is to determine the therapeutic efficacy of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in aged APPswe/PS1dE9 (APP/PS1) mice. SCF+G-CSF was subcutaneously injected for 12 days to 25-month-old male APP/PS1 mice. We observed that SCF+G-CSF treatment reduced the Aβ plaques in both the cortex and hippocampus. SCF+G-CSF treatment increased the association of TREM2+/Iba1+ cells with Aβ plaques and enhanced Aβ uptake by Iba1+ and CD68+cells in the brains of aged APP/PS1 mice. Importantly, cerebral expression area of P2RY12+and TMEM119+ homeostatic microglia and the branches of P2RY12+ homeostatic microglia were increased in the SCF+G-CSF-treated aged APP/PS1 mice. SCF+G-CSF treatment also decreased NOS-2 and increased IL-4 in the brains of aged APP/PS1 mice. Moreover, the loss of MAP2+dendrites and PSD-95+post-synapses and the accumulation of aggregated tau in the brains of aged APP/PS1 mice were ameliorated by SCF+G-CSF treatment. Furthermore, the density of P2RY12+ microglia was negatively correlated with Aβ deposits, but positively correlated with the densities of MAP2+ dendrites and PSD-95+ puncta in the brains of aged APP/PS1 mice. These findings reveal the therapeutic potential of SCF+G-CSF treatment in ameliorating AD pathology at the late stage.

Keywords Alzheimer’s disease      β-amyloid      granulocyte colony-stimulating factor      stem cell factor      microglia      neuroinflammation     
Corresponding Authors: Zhao Li-Ru   
About author:

these authors contributed equally to this work.

Just Accepted Date: 11 February 2020   Issue Date: 19 November 2020
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Guo Xingzhi
Liu Yanying
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Zhao Li-Ru
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Guo Xingzhi,Liu Yanying,Morgan David, et al. Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice[J]. Aging and disease, 2020, 11(6): 1423-1443.
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http://www.aginganddisease.org/EN/10.14336/AD.2020.0201     OR
Figure 1.  Experimental flowchart and imaging areas in the brain sections. Mouse brain diagrams illustrate the brain regions and the areas for imaging in the cortex and hippocampus. s.c., subcutaneously; IHC, immunohistochemistry.
Figure 2.  SCF+G-CSF treatment reduces Aβ deposits in the brains of aged APP/PS1 mice. (A) Representative images of 4G8+ (red) Aβ deposits in the cortex and hippocampus with both low magnification and high magnification. (B-D) Quantification data show the percentage of 4G8+ Aβ area (B), the number of 4G8+ Aβ plaques (C) and the average size of 4G8+ Aβ plaques (D) in the cortex of aged APP/PS1 male mice treated with or without SCF+G-CSF. (E-G) Quantification data illustrate the percentage of 4G8+ Aβ area (E), the number of 4G8+ Aβ plaques (F) and the average size of 4G8+ Aβ plaques (G) in the hippocampus of aged APP/PS1 mice treated with or without SCF+G-CSF. Blue: Nuclear counterstaining by 4',6-diamidino-2-phenylindole (DAPI). SG: SCF+G-CSF. N=4-5. Mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 by Student’s t-test.
Figure 3.  SCF+G-CSF treatment decreases fibrillar Aβ deposits and increases blood vessel density in the brains of aged APP/PS1 mice. (A) Representative confocal images show X-34+ fibrillar Aβ plaques (blue) and collagen IV (Col-IV) immunopositive blood vessels (red) in the cortex and hippocampal CA1 region of aged APP/PS1 mice and age-matched wild type (WT) mice. (B and C) Quantification data show the number of X-34+ fibrillar Aβ plaques (B) and the percentage of X-34+ fibrillar Aβ area (C) in the cortex and hippocampal CA1 of aged APP/PS1 mice. (D) Quantification data show the percentage of Col-IV+ area in the cortex and hippocampal CA1 of aged APP/PS1 mice and age-matched WT mice. N=4-5. Mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 by Student’s t-test (B, C) or one-way ANOVA followed by Fisher’s LSD post hoc test.
Figure 4.  SCF+G-CSF treatment increases TREM2 expression in the Iba1+ microglia/macrophages surrounding the 6E10+ senile plaques. (A) Representative confocal images of TREM2 (red), 6E10 (purple) and Iba1 (green) triple immunofluorescence staining in the brains of aged APP/PS1 mice. Blue: Nuclear counterstaining by DAPI. (B) Representative orthographic view of z-stack images (12 z-stacks with 1μm intervals) illustrates the location and interaction of TREM2 + cells (red) and 6E10+ Aβ plaques (white) in the brains of aged APP/PS1 mice. (C) Quantification data show the percentage of TREM2+ area surrounding the 6E10+ Aβ plaques (within 10μm from the border of the Aβ plaques) in the brains of aged APP/PS1 mice with or without SCF+G-CSF treatment. (D) Representative orthographic view of z-stack images (12 z-stacks with 1μm intervals) displays the location and interaction of TREM2+/Iba1+ co-expressing cells (yellow) and 6E10+ Aβ plaques (white) in the brains of APP/PS1 mice. (E) Quantification data show the percentage of TREM2+/Iba1+ co-expression area in the total of Iba1+ area in the vicinity of 6E10+ Aβ plaques in the brains of aged APP/PS1 mice with or without SCF+G-CSF treatment. N=4-5. Mean ± SEM. * p<0.05 by Student’s t-test.
Figure 5.  SCF+G-CSF treatment increases the association of Iba1+ microglia/macrophages with senile plaques and enhances uptake of 4G8+ Aβ by the Iba1+ microglia/macrophages in the brains of aged APP/PS1 mice. (A) Representative confocal images illustrate the association of Iba1+ cells (green) with 4G8+ Aβ plaques (red) in the brains of aged APP/PS1 mice. Blue: Nuclear counterstaining by DAPI. (B) Quantification of the percentage of Iba1+ area in/surrounding the 4G8+ Aβ plaques in the brains of aged APP/PS1 mice with or without SCF+G-CSF treatment. (C) Representative 3-dimensional projected images reveal the overlapped (yellow) Iba1+ cells (green) with 4G8+ Aβ (red) in the brains of aged APP/PS1 mice. The white arrows indicate the co-expression (yellow) of 4G8+ Aβ and Iba1+ cells in the brains of aged APP/PS1 mice. (D and E) Representative orthographic view of z-stack images (12 z-stacks with 1μm intervals) shows the co-expression (yellow) of 4G8+ Aβ (red) and Iba1+ cells (green) in the brains of aged APP/PS1 mice. (F) Quantification data present the percentage of 4G8+ Aβ volume within the Iba1+ cells in the brains of aged APP/PS1 mice treated with or without SCF+G-CSF. N=4-5. Mean ± SEM. *p<0.05 by Student’s t-test.
Figure 6.  SCF+G-CSF treatment modulates the expression of P2RY12 in the brains of aged APP/PS1 mice. (A) Representative confocal images show P2RY12 (green) and 6E10 (red) double immunofluorescence staining in the cortex and hippocampal CA1 of aged APP/PS1 mice and age-matched wild type (WT) mice. (B and C) Quantification data reveal the percentage of P2RY12+ area in the cortex (B) and CA1 region (C) in aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched WT control mice. N=4-5. Mean ± SEM. ***p<0.001, one-way ANOVA followed by Fisher’s LSD post hoc test. (D) Representative confocal images illustrate the P2RY12 (green) expressing Iba1+ (red) cells within and outside the 6E10+ Aβ plaques (cyan) in the brains of aged APP/PS1 mice and age-matched WT mice. Dash line: separate the area of the vicinity and outside of Aβ plaques. (E) Quantification data show the percentage of P2RY12+/Iba1+co-expressing area within and arround the 6E10+ Aβ plaques in the brains of aged APP/PS1 mice treated with or without SCF+G-CSF. (F) Quantification data present the percentage of P2RY12+/Iba1+co-expressing area outside the 6E10+ Aβ plaques (10μm away from the border of Aβ plaques) in the brains of aged APP/PS1 mice treated with or without SCF+G-CSF. N=4-5. Mean ± SEM. *p<0.05, **p<0.01 by Student’s t-test. (G) The number of branches in the P2RY12+ microglia outside the 6E10+ Aβ plaques is quantified by Sholl analysis. Blue: Nuclear counterstaining by DAPI. N=4-5. Mean ± SEM. APP/PS1 vs. APP/PS1+SG: *p<0.05, **p<0.01, ***p<0.001; APP/PS1 vs. WT: #p<0.05, ##p<0.01, ###p<0.001 by One-way ANOVA followed by Fisher’s LSD post hoc test.
Figure 7.  SCF+G-CSF treatment decreases NOS-2 expression and increases IL-4 expression in the brains of aged APP/PS1 mice. (A) Representative confocal images illustrate the NOS-2 immunopositive staining (red) in the cortex and hippocampal CA1 of aged APP/PS1 mice treated with or without SCF+G-CSF and age-matched wild type (WT) mice. (B) Quantification data show the percentage of NOS-2+ area in the cortex and CA1 region of aged APP/PS1mice (with or without SCF+G-CSF treatment) and age-matched WT mice. (C) Representative confocal images illustrate the IL-4 immunopositive staining (red) in the cortex and CA1 region of aged APP/PS1 mice treated with or without SCF+G-CSF and age-matched WT mice. (D) Quantification data show the percentage of IL-4+ area in the cortex and CA1 of aged APP/PS1 mice treated with or without SCF+G-CSF and age-matched WT control mice. Blue: Nuclear counterstaining by DAPI. N=4-5. Mean ± SEM. *p<0.05, ***p<0.001, one-way ANOVA followed by Fisher’s LSD post hoc test.
Figure 8.  SCF+G-CSF treatment increases dendritic density in the cortex and hippocampus of aged APP/PS1 mice. (A) Representative tile scanning confocal images show MAP2 immunopositive dendrites (red) in the entire cortex of aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched wild type (WT) mice. (B) Quantification data show the changes in the percentage of MAP2+ area in the cortex among aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched WT mice. (C) Representative tile scanning confocal images illustrate MAP2 immunopositive dendrites (red) in the CA1 region of aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched WT mice. (D) Quantification data reveal the changes in the percentage of MAP2+ area in the CA1 region among aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched WT mice. Blue: Nuclear counterstaining by DAPI. N=4-5. Mean ± SEM. *p<0.05, **p<0.01, one-way ANOVA followed by Fisher’s LSD post hoc test.
Figure 9.  SCF+G-CSF treatment increases PSD-95 positive post-synapses in the cortex and hippocampus of aged APP/PS1 mice. (A) Representative confocal images show PSD-95 immunopositive puncta (red) in the cortex and hippocampal CA1 of aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched wild type (WT) mice. (B and C) Quantification data show the changes of PSD-95+ puncta in the cortex (B) and hippocampal CA1 (C) among aged APP/PS1 mice treated with/without SCF+G-CSF and age-matched WT mice. N=4-5. Mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, one-way ANOVA followed by Fisher’s LSD post hoc test.
Figure 10.  Correlation between Aβ plaques, homeostatic microglia, dendrites and synapses in the brains of aged APP/PS1 mice treated with or without SCF+G-CSF. (A and B) P2RY12+ homeostatic microglia show a significantly negative correlation with X-34+ fibrillar Aβ plaques in the cortex (r = -0.776, p<0.05) (A) and hippocampal CA1 (r = -0.712, p<0.05) (B). Note that increased P2RY12+ resting microglia are correlated with the reduced X-34+ fibrillar Aβ plaques in the cortex and hippocampal CA1 in the SCF+G-CSF-treated aged APP/PS1 mice. (C and D) P2RY12+ microglia display a positive correlation with MAP2+ dendrites in the cortex (r=0.831, p<0.01) (C) and hippocampal CA1 (r=0.663, p=0.051) (D). Note that increased P2RY12+ homeostatic microglia are correlated with the increased MAP2+ dendrites in the cortex and CA1 in the SCF+G-CSF-treated aged APP/PS1 mice. (E and F) P2RY12+ microglia show a significantly positive correlation with PSD-95+ puncta in the cortex (r=0.854, p<0.01) (E) and hippocampal CA1 (r=0.928, p<0.001) (F). Note that the increased P2RY12+ homeostatic microglia are correlated with the increased PSD-95+ puncta in the cortex and CA1 in the SCF+G-CSF-treated aged APP/PS1 mice.
[1] Nichols E, Szoeke CE, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. (2019). Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology, 18:88-106.
[2] Gaugler J, James B, Johnson T, Marin A, Weuve J (2019). 2019 Alzheimer's disease facts and figures. ALZHEIMERS & DEMENTIA, 15:321-387.
[3] Armstrong RA (2006). Plaques and tangles and the pathogenesis of Alzheimer's disease. Folia Neuropathol, 44:1-11.
[4] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurol, 14:388-405.
[5] Vetrivel KS, Thinakaran G (2006). Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology, 66:S69-73.
[6] Palop JJ, Mucke L (2010). Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci, 13:812-818.
[7] Diaz A, Limon D, Chavez R, Zenteno E, Guevara J (2012). Abeta25-35 injection into the temporal cortex induces chronic inflammation that contributes to neurodegeneration and spatial memory impairment in rats. J Alzheimers Dis, 30:505-522.
[8] Pujadas L, Rossi D, Andres R, Teixeira CM, Serra-Vidal B, Parcerisas A, et al. (2014). Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. Nat Commun, 5:3443.
[9] Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. (2000). A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature, 408:979-982.
[10] Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, et al. (2016). The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med, 8:363ra150.
[11] Graham WV, Bonito-Oliva A, Sakmar TP (2017). Update on Alzheimer's Disease Therapy and Prevention Strategies. Annu Rev Med, 68:413-430.
[12] Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, et al. (2016). The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature, 537:50-56.
[13] van Dyck CH (2018). Anti-Amyloid-beta Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise. Biol Psychiatry, 83:311-319.
[14] Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, et al. (2003). Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci, 23:3745-3751.
[15] Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, et al. (2004). Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation, 1:24.
[16] Morgan D (2011). Immunotherapy for Alzheimer’s disease. Journal of Internal Medicine, 269:54-63.
[17] Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. (2009). A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology, 73:2061-2070.
[18] Schneider L (2020). A resurrection of aducanumab for Alzheimer's disease. The Lancet Neurology, 19:111-112.
[19] Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, et al. (2002). Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science, 298:1379.
[20] Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, et al. (1985). Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proceedings of the National Academy of Sciences, 82:1526-1530.
[21] Zsebo KM, Wypych J, McNiece IK, Lu HS, Smith KA, Karkare SB, et al. (1990). Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver-conditioned medium. Cell, 63:195-201.
[22] Duarte RF, Frank DA (2000). SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways. Blood, 96:3422-3430.
[23] Briddell R, Hartley C, Smith K, McNiece I (1993). Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential. Blood, 82:1720-1723.
[24] Duarte RF, Franf DA (2002). The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance. Leuk Lymphoma, 43:1179-1187.
[25] Hess DA, Levac KD, Karanu FN, Rosu-Myles M, White MJ, Gallacher L, et al. (2002). Functional analysis of human hematopoietic repopulating cells mobilized with granulocyte colony-stimulating factor alone versus granulocyte colony-stimulating factor in combination with stem cell factor. Blood, 100:869-878.
[26] Su Y, Cui L, Piao C, Li B, Zhao LR (2013). The effects of hematopoietic growth factors on neurite outgrowth. PLoS One, 8:e75562.
[27] Zhao L-R, Berra HH, Duan W-M, Singhal S, Mehta J, Apkarian AV, et al. (2007). Beneficial effects of hematopoietic growth factor therapy in chronic ischemic stroke in rats. Stroke, 38:2804-2811.
[28] Cui L, Murikinati SR, Wang D, Zhang X, Duan WM, Zhao LR (2013). Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke. PLoS One, 8:e64684.
[29] Cui L, Duchamp NS, Boston DJ, Ren X, Zhang X, Hu H, et al. (2015). NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke. Experimental neurology, 263:17-27.
[30] Laske C, Stellos K, Stransky E, Seizer P, Akcay O, Eschweiler GW, et al. (2008). Decreased plasma and cerebrospinal fluid levels of stem cell factor in patients with early Alzheimer's disease. J Alzheimers Dis, 15:451-460.
[31] Laske C, Stellos K, Stransky E, Leyhe T, Gawaz M (2009). Decreased plasma levels of granulocyte-colony stimulating factor (G-CSF) in patients with early Alzheimer's disease. J Alzheimers Dis, 17:115-123.
[32] Li B, Gonzalez-Toledo ME, Piao CS, Gu A, Kelley RE, Zhao LR (2011). Stem cell factor and granulocyte colony-stimulating factor reduce beta-amyloid deposits in the brains of APP/PS1 transgenic mice. Alzheimers Res Ther, 3:8.
[33] Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001). Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng, 17:157-165.
[34] Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet, 13:159-170.
[35] Zhao LR, Navalitloha Y, Singhal S, Mehta J, Piao CS, Guo WP, et al. (2007). Hematopoietic growth factors pass through the blood-brain barrier in intact rats. Exp Neurol, 204:569-573.
[36] Zhao LR, Berra HH, Duan WM, Singhal S, Mehta J, Apkarian AV, et al. (2007). Beneficial effects of hematopoietic growth factor therapy in chronic ischemic stroke in rats. Stroke, 38:2804-2811.
[37] Piao CS, Gonzalez-Toledo ME, Gu X, Zhao LR (2012). The combination of stem cell factor and granulocyte-colony stimulating factor for chronic stroke treatment in aged animals. Exp Transl Stroke Med, 4:25.
[38] Spillantini MG, Goedert M, Jakes R, Klug A (1990). Different configurational states of beta-amyloid and their distributions relative to plaques and tangles in Alzheimer disease. Proc Natl Acad Sci U S A, 87:3947-3951.
[39] Serpell LC (2000). Alzheimer's amyloid fibrils: structure and assembly. Biochim Biophys Acta, 1502:16-30.
[40] Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, et al. (2017). Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin, 38:1205-1235.
[41] Kress GJ, Liao F, Dimitry J, Cedeno MR, FitzGerald GA, Holtzman DM, et al. (2018). Regulation of amyloid-beta dynamics and pathology by the circadian clock. J Exp Med, 215:1059-1068.
[42] Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, et al. (2019). Vascular Dysfunction in Alzheimer's Disease: A Prelude to the Pathological Process or a Consequence of It? J Clin Med, 8.
[43] Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS, et al. (2014). Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease. Neuropsychopharmacology, 39:2949-2962.
[44] Kim SM, Mun BR, Lee SJ, Joh Y, Lee HY, Ji KY, et al. (2017). TREM2 promotes Abeta phagocytosis by upregulating C/EBPalpha-dependent CD36 expression in microglia. Sci Rep, 7:11118.
[45] Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobryshev YV (2017). CD68/macrosialin: not just a histochemical marker. Lab Invest, 97:4-13.
[46] Wilkinson K, El Khoury J (2012). Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimers Dis, 2012:489456.
[47] Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, et al. (2013). Inflammatory components in human Alzheimer's disease and after active amyloid-beta42 immunization. Brain, 136: 2677-2696.
[48] Daria A, Colombo A, Llovera G, Hampel H, Willem M, Liesz A, et al. (2017). Young microglia restore amyloid plaque clearance of aged microglia. EMBO J, 36:583-603.
[49] Koenigsknecht-Talboo J, Landreth GE (2005). Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci, 25:8240-8249.
[50] Spangenberg EE, Green KN (2017). Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models. Brain Behav Immun, 61:1-11.
[51] Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. (2014). Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci, 17:131-143.
[52] Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, et al. (2015). Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol, 77:75-99.
[53] Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H (2017). Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis. Brain, 140:1900-1913.
[54] Nimmerjahn A, Kirchhoff F, Helmchen F (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308:1314-1318.
[55] Rao Y, Liang YX, Peng B (2017). A revisit of rod microglia in preclinical studies. Neural Regen Res, 12:56-57.
[56] Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. (2007). Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci, 27:796-807.
[57] Sanjari Moghaddam H, Aarabi MH (2018). Abeta-Mediated Dysregulation of F-Actin Nanoarchitecture Leads to Loss of Dendritic Spines and Alzheimer's Disease-Related Cognitive Impairments. J Neurosci, 38:5840-5842.
[58] Thal DR, Griffin WS, Braak H (2008). Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. J Cell Mol Med, 12:1848-1862.
[59] Metaxas A, Thygesen C, Kempf SJ, Anzalone M, Vaitheeswaran R, Petersen S, et al. (2019). Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease. Sci Rep, 9:15758.
[60] Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013). Origin and differentiation of microglia. Front Cell Neurosci, 7:45.
[61] Streit WJ, Braak H, Xue QS, Bechmann I (2009). Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol, 118:475-485.
[62] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell, 169:1276-1290 e1217.
[63] Navarro V, Sanchez-Mejias E, Jimenez S, Munoz-Castro C, Sanchez-Varo R, Davila JC, et al. (2018). Microglia in Alzheimer's Disease: Activated, Dysfunctional or Degenerative. Front Aging Neurosci, 10:140.
[64] Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, et al. (2019). The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Abeta Plaques. Cell Rep, 27:1293-1306 e1296.
[65] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. (2017). The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity, 47:566-581 e569.
[66] Sanchez-Mejias E, Navarro V, Jimenez S, Sanchez-Mico M, Sanchez-Varo R, Nunez-Diaz C, et al. (2016). Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration. Acta Neuropathol, 132:897-916.
[67] Hemonnot AL, Hua J, Ulmann L, Hirbec H (2019). Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities. Front Aging Neurosci, 11:233.
[68] Monasor LS, Müller SA, Colombo A, König J, Roth S, Liesz A, et al. (2019). Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. bioRxiv.
[69] Colonna M, Wang Y (2016). TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci, 17:201-207.
[70] Boissonneault V, Filali M, Lessard M, Relton J, Wong G, Rivest S (2009). Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease. Brain, 132:1078-1092.
[71] Boyd TD, Bennett SP, Mori T, Governatori N, Runfeldt M, Norden M, et al. (2010). GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis, 21:507-518.
[72] Smith AM, Gibbons HM, Oldfield RL, Bergin PM, Mee EW, Curtis MA, et al. (2013). M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia. J Neuroinflammation, 10:85.
[73] Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, et al. (2009). Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience, 163:55-72.
[74] Sanchez-Ramos J, Cimino C, Avila R, Rowe A, Chen R, Whelan G, et al. (2012). Pilot study of granulocyte-colony stimulating factor for treatment of Alzheimer's disease. J Alzheimers Dis, 31:843-855.
[75] Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron, 49:489-502.
[76] Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, et al. (2007). Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell, 18:1490-1496.
[77] Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, et al. (2018). The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol Neurodegener, 13:29.
[78] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. (2013). Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med, 368:107-116.
[79] Garcia-Revilla J, Alonso-Bellido IM, Burguillos MA, Herrera AJ, Espinosa-Oliva AM, Ruiz R, et al. (2019). Reformulating Pro-Oxidant Microglia in Neurodegeneration. J Clin Med, 8.
[80] Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. (2015). TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med, 212:287-295.
[81] Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, et al. (2018). Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease. Mol Neurodegener, 13:24.
[82] Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, et al. (2006). The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci, 9:1512-1519.
[83] Lai MK, Tan MG, Kirvell S, Hobbs C, Lee J, Esiri MM, et al. (2008). Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer's disease neuropathology. J Neural Transm (Vienna), 115:1165-1172.
[84] Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, et al. (1998). Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol, 152:307-317.
[85] Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N, et al. (2007). Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol, 2:222-231.
[86] Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, et al. (1999). Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging, 20:581-589.
[87] Casali BT, Reed-Geaghan EG, Landreth GE (2018). Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer's disease. J Neuroinflammation, 15:43.
[88] Yuskaitis CJ, Jope RS (2009). Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal, 21:264-273.
[89] Lyons A, Griffin RJ, Costelloe CE, Clarke RM, Lynch MA (2007). IL-4 attenuates the neuroinflammation induced by amyloid-beta in vivo and in vitro. J Neurochem, 101:771-781.
[90] Pfeilschifter J (2002). Nitric oxide triggers the expression of proinflammatory and protective gene products in mesangial cells and the inflamed glomerulus. Nephrol Dial Transplant, 17:347-348.
[91] Kalinin S, Polak PE, Madrigal JL, Gavrilyuk V, Sharp A, Chauhan N, et al. (2006). Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist. Antioxid Redox Signal, 8:873-883.
[92] Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493:674-678.
[93] Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. (2013). Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A, 110:E2518-2527.
[94] Zou C, Shi Y, Ohli J, Schuller U, Dorostkar MM, Herms J (2016). Neuroinflammation impairs adaptive structural plasticity of dendritic spines in a preclinical model of Alzheimer's disease. Acta Neuropathol, 131:235-246.
[95] Lim RW, Halpain S (2000). Regulated association of microtubule-associated protein 2 (MAP2) with Src and Grb2: evidence for MAP2 as a scaffolding protein. J Biol Chem, 275:20578-20587.
[96] Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, et al. (2012). TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol, 45:440-454.
[97] Qiao J, Wang J, Wang H, Zhang Y, Zhu S, Adilijiang A, et al. (2016). Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model. Glia, 64:240-254.
[98] Woo JA, Boggess T, Uhlar C, Wang X, Khan H, Cappos G, et al. (2015). RanBP9 at the intersection between cofilin and Abeta pathologies: rescue of neurodegenerative changes by RanBP9 reduction. Cell Death Dis, 6:1676.
[99] Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, et al. (2015). Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. Mol Neurodegener, 10:58.
[100] Biscaro B, Lindvall O, Tesco G, Ekdahl CT, Nitsch RM (2012). Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease. Neurodegener Dis, 9:187-198.
[101] Baalman K, Marin MA, Ho TS, Godoy M, Cherian L, Robertson C, et al. (2015). Axon initial segment-associated microglia. J Neurosci, 35:2283-2292.
[102] Miyamoto A, Wake H, Moorhouse AJ, Nabekura J (2013). Microglia and synapse interactions: fine tuning neural circuits and candidate molecules. Front Cell Neurosci, 7:70.
[103] Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011). The role of microglia in the healthy brain. J Neurosci, 31:16064-16069.
[104] Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013). Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci, 36:209-217.
[105] Jadhav S, Cubinkova V, Zimova I, Brezovakova V, Madari A, Cigankova V, et al. (2015). Tau-mediated synaptic damage in Alzheimer's disease. Transl Neurosci, 6:214-226.
[106] Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Gotz J (2018). Amyloid-beta and tau complexity - towards improved biomarkers and targeted therapies. Nat Rev Neurol, 14:22-39.
[107] Ittner A, Ittner LM (2018). Dendritic Tau in Alzheimer's Disease. Neuron, 99:13-27.
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