Abstract
The role of neuroinflammation in the pathogenesis of neurodegenerative diseases has become more evident in recent years. Research on the etiology and pathogenesis of sporadic Alzheimer’s disease (AD) has focused on the role of chemokines such as CX3CL1, on the triggering receptors expressed by myeloid cells (TREMs), especially TREM2, and on the transcription factor/nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ). Here we analyzed the expression levels of CX3CL1, TREM2, and PPARγ in tissue homogenates from human brain regions that have different degrees of vulnerability to neuropathological AD-related changes to obtain insights into the pathogenesis and progression of AD. We found that CX3CL1 and TREM2, two genes related to neuroinflammation, are more highly expressed in brain regions with pronounced vulnerability to AD-related changes, such as the hippocampus, and that the expression levels reflect the course of the disease, whereas regions with low vulnerability to AD, seemed generally less affected by neuroinflammation. Furthermore, our results support previous findings of significantly higher CX3CL1 plasma levels in patients with mild to moderate AD than in patients with severe AD. Thus, CX3CL1 should be considered as promising additional marker for the early diagnosis of AD and underlines once more, the involvement of the neuroinflammation in the pathogenesis of this neurodegenerative disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339(6116):156–161. doi:10.1126/science.1227901
Aleshin S, Reiser G (2013) Role of the peroxisome proliferator-activated receptors (PPAR)-alpha, beta/delta and gamma triad in regulation of reactive oxygen species signaling in brain. Biol Chem 394(12):1553–1570. doi:10.1515/hsz-2013-0215
Attems J, Thomas A, Jellinger K (2012) Correlations between cortical and subcortical tau pathology. Neuropathol Appl Neurobiol 38(6):582–590. doi:10.1111/j.1365-2990.2011.01244.x
Bartl J, Monoranu CM, Wagner AK, Kolter J, Riederer P, Grunblatt E (2013) Alzheimer’s disease and type 2 diabetes: two diseases, one common link? World J Biol Psychiatry 14(3):233–240. doi:10.3109/15622975.2011.650204
Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385(6617):640–644. doi:10.1038/385640a0
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82(4):239–259
Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121(2):171–181. doi:10.1007/s00401-010-0789-4
Braak H, Braak E, Bohl J, Lang W (1989) Alzheimer’s disease: amyloid plaques in the cerebellum. J Neurol Sci 93(2–3):277–287
Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis 37(3):503–509. doi:10.1016/j.nbd.2009.10.006
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924
Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4(4):399–418. doi:10.1007/s11481-009-9164-4
Fallgatter AJ, Neuhauser B, Herrmann MJ, Ehlis AC, Wagener A, Scheuerpflug P, Reiners K, Riederer P (2003) Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J Neural Transm 110(12):1437–1443. doi:10.1007/s00702-003-0087-6
Fallgatter AJ, Ehlis AC, Ringel TM, Herrmann MJ (2005) Age effect on far field potentials from the brain stem after transcutaneous vagus nerve stimulation. Int J Psychophysiol 56(1):37–43
Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, Levine AP, Hardy J, Pocock JM, Guerreiro R, Weale ME, Ryten M (2013) Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging 34(12):2699–2714. doi:10.1016/j.neurobiolaging.2013.05.001
Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94(9):4312–4317
Grinberg LT, Rueb U, Heinsen H (2011) Brainstem: neglected locus in neurodegenerative diseases. Front Neurol 2:42. doi:10.3389/fneur.2011.00042
Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28(3):327–335
Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU (2002) Fractalkine and fractalkine receptors in human neurons and glial cells. J Neurosci Res 69(3):418–426. doi:10.1002/jnr.10304
Hickman SE, El Khoury J (2014) TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharmacol 88(4):495–498. doi:10.1016/j.bcp.2013.11.021
Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109(4):1144–1156. doi:10.1111/j.1471-4159.2009.06042.x
Kim TS, Lim HK, Lee JY, Kim DJ, Park S, Lee C, Lee CU (2008) Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 436(2):196–200. doi:10.1016/j.neulet.2008.03.019
Larner AJ (1997) The cerebellum in Alzheimer’s disease. Dement Geriatr Cogn Disord 8(4):203–209
Lue LF, Schmitz C, Walker DG (2014a) What happens to microglial TREM2 in Alzheimer’s disease: Immunoregulatory turned into immunopathogenic? Neuroscience. doi:10.1016/j.neuroscience.2014.09.050
Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG (2014b) TREM2 protein expression changes correlate with Alzheimer’s disease neurodegenerative pathologies in post-mortem temporal cortices. Brain Pathol. doi:10.1111/bpa.12190
Mandrekar-Colucci S, Landreth GE (2011) Nuclear receptors as therapeutic targets for Alzheimer’s disease. Expert Opin Ther Targets 15(9):1085–1097. doi:10.1517/14728222.2011.594043
Mandrekar-Colucci S, Karlo JC, Landreth GE (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 32(30):10117–10128. doi:10.1523/JNEUROSCI.5268-11.2012
Mavroudis IA, Fotiou DF, Adipepe LF, Manani MG, Njau SD, Psaroulis D, Costa VG, Baloyannis SJ (2010) Morphological changes of the human purkinje cells and deposition of neuritic plaques and neurofibrillary tangles on the cerebellar cortex of Alzheimer’s disease. Am J Alzheimers Dis Other Demen 25(7):585–591. doi:10.1177/1533317510382892
Nomura S, Mizuno N (1983) Central distribution of efferent and afferent components of the cervical branches of the vagus nerve. A HRP study in the cat. Anat Embryol (Berl) 166(1):1–18
Polak T, Ehlis AC, Langer JB, Plichta MM, Metzger F, Ringel TM, Fallgatter AJ (2007) Non-invasive measurement of vagus activity in the brainstem: a methodological progress towards earlier diagnosis of dementias? J Neural Transm 114(5):613–619. doi:10.1007/s00702-007-0625-8
Reaux-Le Goazigo A, Van Steenwinckel J, Rostene W, Melik Parsadaniantz S (2013) Current status of chemokines in the adult CNS. Prog Neurobiol 104:67–92
Rosenthal SL, Kamboh MI (2014) Late-onset Alzheimer’s disease genes and the potentially implicated pathways. Curr Genet Med Rep 2:85–101. doi:10.1007/s40142-014-0034-x
Schwaeble WJ, Stover CM, Schall TJ, Dairaghi DJ, Trinder PK, Linington C, Iglesias A, Schubart A, Lynch NJ, Weihe E, Schafer MK (1998) Neuronal expression of fractalkine in the presence and absence of inflammation. FEBS Lett 439(3):203–207
Sheridan GK, Murphy KJ (2013) Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage. Open Biol 3(12):130181. doi:10.1098/rsob.130181
Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–657
Williamson LL, Bilbo SD (2013) Chemokines and the hippocampus: a new perspective on hippocampal plasticity and vulnerability. Brain Behav Immun 30:186–194. doi:10.1016/j.bbi.2013.01.077
Acknowledgments
This work was supported by grants from the “Dr. med. Edda Neele-Stiftung”, Frankfurt/Main, Germany and from the Interdisciplinary Center for Clinical Research (IZKF), University of Wuerzburg, Germany.
Conflict of interest
The authors have no actual or potential conflicts of interest to disclose.
Author information
Authors and Affiliations
Corresponding author
Additional information
S. Strobel and E. Grünblatt contributed equally to this study.
Rights and permissions
About this article
Cite this article
Strobel, S., Grünblatt, E., Riederer, P. et al. Changes in the expression of genes related to neuroinflammation over the course of sporadic Alzheimer’s disease progression: CX3CL1, TREM2, and PPARγ. J Neural Transm 122, 1069–1076 (2015). https://doi.org/10.1007/s00702-015-1369-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-015-1369-5