Tph2 Genetic Ablation Contributes to Senile Plaque Load and Astrogliosis in APP/PS1 Mice

Author(s): Chao-Jin Xu, Jun-Ling Wang, Jing-Pan, Min-Liao*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 3 , 2019

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Abstract:

Background: Amyloid-β (Aβ) accumulation plays a critical role in the pathogenesis of Alzheimer’s disease (AD) lesions. Deficiency of Serotonin signaling recently has been linked to the increased Aβ level in transgenic mice and humans. In addition, tryptophan hydroxylase-2 (Tph2), a second tryptophan hydroxylase isoform, controls brain serotonin synthesis. However, it remains to be determined that whether Tph2 deficient APP/PS1mice affect the formation of Aβ plaques in vivo.

Methods: Both quantitative and qualitative immunochemistry methods, as well as Congo red staining were used to evaluate the Aβ load and astrogliosis in these animals.

Results: we studied alterations of cortex and hippocampus in astrocytes and senile plaques by Tph2 conditional knockout (Tph2 CKO) AD mice from 6-10 months of age. Using Congo red staining and immunostained with Aβ antibody, we showed that plaques load or plaques numbers significantly increased in Tph2 CKO experimental groups at 8 to 10 months old, compared to wild type (WT) group, respectively. Using GFAP+ astrocytes immunofluorescence method, we found that the density of GFAP+ astrocytes markedly enhanced in Tph2 CKO at 10 months. We showed Aβ plaques co-localized autophagic markers LC3 and p62. Nevertheless, we did not observe any co-localization between GFAP+ astrocytes and autophagic markers, but detected the co-localization between βIII-tubulin+ neurons and autophagic markers.

Conclusion: Overall, our work provides the preliminary evidence in vivo that Tph2 plays a role in amyloid plaques generation.

Keywords: Tph2, Aβ plaque, APP/PS1, autophagy, astrocyte, Alzheimer's disease.

[1]
Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis. J Neuroinflam 8(1): 150. (2011)
[2]
Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8: 112. (2014)
[3]
Jie Z, O’Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis. J Neuroinflam 8(1): 1-17. (2011)
[4]
Li L, Liu J, Suo WZ. GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice. J Neuroinflam 5(1): 24. (2008)
[5]
Abhishek S, Marco BD, Uday K. Innate immunity and neuroinflammation. Mediat Inflam 2013(6): 342931. (2013)
[6]
Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20(15): 5709-14. (2000)
[7]
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4): 388-405. (2015)
[8]
Higgins CE, Gross SS. Chapter 6 - Tetrahydrobiopterin: An Essential Cofactor for Nitric Oxide Synthases and Amino Acid Hydroxylases. In: Nitric Oxide(Second Edition) (Ed: Ignarro LJ) San Diego: Academic Press;. 169-209. (2010)
[9]
Xu C-J, Peng Z, Dai T-L, Niu X-Y, Wang J-L, Jin M-S, et al. Evaluation of blood-brain barrier permeability in tryptophan hydroxylase 2-knockout mice. Exp Ther Med 8(5): 1467-70. (2014)
[10]
Byrne JH, Heidelberger R, Waxham MN. In: From molecules to networks An introduction to cellular and molecular neuroscience With CD-ROM Elsevier Academic Press. (2014)
[11]
Chen GL, Miller GM. Tryptophan hydroxylase-2: an emerging therapeutic target for stress disorders. Biochem Pharmacol 85(9): 1227-33. (2013)
[12]
Gershon MD. Serotonin is a sword and a shield of the bowel: serotonin plays offense and defense. Trans Am Clin Climatolog Assoc 123: 268. (2012)
[13]
Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N. Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 33(19): 8270-5. (2013)
[14]
Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci USA 108(36): 14968-73. (2011)
[15]
Gelman DM, Noaín D, Avale ME, Otero V, Low MJ, Rubinstein M. Transgenic mice engineered to target Cre/loxP-mediated DNA recombination into catecholaminergic neurons. Genesis 36(4): 196-02. (2003)
[16]
Song NN, Jia YF, Zhang L, Zhang Q, Huang Y, Liu XZ, et al. Reducing central serotonin in adulthood promotes hippocampal neurogenesis. Sci Rep 6: 20338. (2016)
[17]
Kriegebaum C, Song NN, Gutknecht L, Huang Y, Schmitt A, Reif A, et al. Brain-specific conditional and time-specific inducible Tph2 knockout mice possess normal serotonergic gene expression in the absence of serotonin during adult life. Neurochem Int 57(5): 512-7. (2010)
[18]
Wilcock DM, Gordon MN, Morgan D. Quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with Congo red histochemical stain. Nat Protoc 1(3): 1591-5. (2006)
[19]
Beauquis J, Pavía P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, et al. Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol 239: 28-37. (2013)
[20]
Paxinos G, Paxinos G. Mouse Brain in Stereotaxic Coordinates 3rd edition, compact version Elsevier Ltd Oxford. (2008)
[21]
Qiao J, Wang J, Wang H, Zhang Y, Zhu S, Adilijiang A, et al. Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model. Glia 64(2): 240-54. (2016)
[22]
Cheng S, Cao D, Hottman DA, Yuan L, Bergo MO, Li L. Farnesyltransferase haplodeficiency reduces neuropathology and rescues cognitive function in a mouse model of Alzheimer disease. J Biol Chem 288(50): 35952-60. (2013)
[23]
Toledo E, Inestrosa N. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer’s disease. Mol Psychiat 15(3): 272-85. (2010)
[24]
Lin T, Liu Y, Shi M, Liu X, Li L, Liu Y, et al. Promotive effect of ginsenoside Rd on proliferation of neural stem cells in vivo and in vitro. J Ethnopharmacol 142(3): 754-61. (2012)
[25]
Calhoun ME, Wiederhold K-H, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, et al. Neuron loss in APP transgenic mice. Nature 395(6704): 755-6. (1998)
[26]
Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C. Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease. Nat Comm 4: 1495. (2013)
[27]
Watson RE Jr, Wiegand SJ, Clough RW, Hoffman GE. Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology. Peptides 7(1): 155-9. (1986)
[28]
Paresce DM, Chung H, Maxfield FR. Slow degradation of aggregates of the Alzheimer’s disease amyloid β-protein by microglial cells. J Biol Chem 272(46): 29390-7. (1997)
[29]
Khurana R, Uversky VN, Nielsen L, Fink AL. Is Congo red an amyloid-specific dye? J Biol Chem 276(25): 22715-21. (2001)
[30]
Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012: 756357. (2012)
[31]
Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239: 133-8. (2013)
[32]
Duffy A, Hölscher C. The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer’s disease. Neuroscience 228: 294-300. (2013)
[33]
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1-42 levels in APPV717I transgenic mice. Brain 128(6): 1442-53. (2005)
[34]
Bains M, Heidenreich KA. Live‐cell imaging of autophagy induction and autophagosome‐lysosome fusion in primary cultured neurons. Meth Enzymol 453: 145-58. (2009)
[35]
Pugsley HR. Assessing autophagic flux by measuring LC3, p62, and LAMP1 co-localization using multispectral imaging flow cytometry. J Vis Exp 2017; (125).
[36]
Roßner S, Lange‐Dohna C, Zeitschel U, Perez‐Polo JR. Alzheimer’s disease β‐secretase BACE1 is not a neuron‐specific enzyme. J Neurochem 92(2): 226-34. (2005)
[37]
Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, inflammation, and immunity: A troika governing cancer and its treatment. Cell 166(2): 288-98. (2016)
[38]
Kurz A, Perneczky R. Amyloid clearance as a treatment target against Alzheimer’s disease. J Alzheimers Dis 4(2): 61-73. (2011)
[39]
Citron M. Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov 9(5): 387-98. (2010)
[40]
Tommonaro G, García-Font N, Vitale RM, Pejin B, Iodice C, Canadas S, et al. Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer’s disease. Eur J Med Chem 122: 326-38. (2016)
[41]
Pejin B, Iodice C, Tommonaro G, De Rosa S. Synthesis and biological activities of thio-avarol derivatives. J Nat Prod 71(11): 1850-3. (2008)
[42]
Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 26(6) (2017)
[43]
Yasuo H, Yasushi T, Masaki I, Atsushi S, Takeshi K, Etsuro M, et al. Type-specific evolution of amyloid plaque and angiopathy in APPsw mice. Neurosci Lett 395(1): 37-41. (2006)
[44]
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, et al. The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22(5): 1858-67. (2002)
[45]
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284): 99-102. (1996)
[46]
Garcia-Alloza M, Hirst WD, Chen CPLH, Lasheras B, Francis PT, Ramírez MJ. Differential involvement of 5-HT1B/1D and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer disease. Neuropsychopharmacol 29: 410. (2003)
[47]
Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, et al. Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer’s disease treatment. Proc Nat Acad Sci USA 111(36): E3825. (2014)
[48]
Lezoualc'H F Robert SJ. The serotonin 5-HT4 receptor and the amyloid precursor protein processing. Exp Gerontol 38(1): 159-66. (2003)
[49]
Gutknecht L, Waider J, Kraft S, Kriegebaum C, Holtmann B, Reif A, et al. Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J Neural Transm 115(8): 1127-32. (2008)
[50]
Tajeddinn W, Persson T, Maioli S, Calvo-Garrido J, Parrado-Fernandez C, Yoshitake T, et al. 5-HT1B and other related serotonergic proteins are altered in APPswe mutation. Neurosci Lett 594: 137-43. (2015)
[51]
Cho S, Hu Y. Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival. Exp Neurol 203(1): 274-8. (2007)
[52]
Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer’s disease AÎ2 peptide. Bioessays 36(6): 570-8. (2014)
[53]
Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, et al. Aβ secretion and plaque formation depend on autophagy. Cell Rep (1): 61-9. (2013)
[54]
Nilsson P, Sekiguchi M, Akagi T, Izumi S, Komori T, Hui K, et al. Autophagy-Related Protein 7 Deficiency in Amyloid β (Aβ) precursor protein transgenic mice decreases aβ in the multivesicular bodies and induces aβ accumulation in the golgi. Am J Pathol 185(2): 305-13. (2015)
[55]
Caccamo A, Ferreira E, Branca C, Oddo S. p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry 22(6): 865-73. (2017)
[56]
Ye J, Jiang Z, Chen X, Liu M, Li J, Liu N. The role of autophagy in pro-inflammatory responses of microglia activation via mitochondrial reactive oxygen species in vitro. J Neurochem 42(2): 215-30. (2017)
[57]
Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 6(5): 237-45. (2007)
[58]
Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Can Therap 10(9): 1533-41. (2011)
[59]
Alpay N, Tekedereli I, Lopez-Berestein G, Dalby K, Ozpolat B. Serotonin signaling plays a role in regulation of autophagy in breast cancer cells. (2011)
[60]
Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE, Razolli DS, et al. Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by alzheimer’s amyloid-î2 oligomers in mice. J Neurosci 36(48): 12106-16. (2016)
[61]
Pomilio C, Pavia P, Gorojod RM, Vinuesa A, Alaimo A, Galvan V, et al. Glial alterations from early to late stages in a model of Alzheimer’s disease: Evidence of autophagy involvement in Aβ internalization. Hippocampus 26(2): 194-210. (2016)
[62]
Natalia A, Dana K, Mihail T, Valentina M, Fatimunnisa Q, Ralph P, et al. Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci USA 106(25): 10332-7. (2009)
[63]
Pratelli M, Pasqualetti M. Serotonergic neurotransmission manipulation for the understanding of brain development and function: learning from Tph2 genetic models Biochimie pii: 50300- 9084(18): 30341-9. (2018)


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Article Details

VOLUME: 16
ISSUE: 3
Year: 2019
Page: [219 - 232]
Pages: 14
DOI: 10.2174/1567205016666190301110110
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