Exposure to a single immobilization or lipopolysaccharide challenge increases expression of genes implicated in the development of Alzheimer’s disease in the mice brain cortex

Open access

Abstract

Objectives. Despite extensive research efforts, mechanisms participating on development of Alzheimer’s disease (AD) are covered only partially. Data from the last decades indicate that various stressors, as etiological factors, may play a role of in the AD. Therefore, we investigated the effect of two acute stressors, immobilization (IMO) and lipopolysaccharide (LPS), on the AD-related neuropathology.

Methods. Adult C57BL/6J mice males were exposed to a single IMO stress or a single intraperitoneal injection of LPS (250 µg/kg body weight). After terminating the experiments, the brains were removed and their cortices isolated. Gene expression of pro-inflammatory cytokines, as well as expression of genes implicated in the AD neuropathology were determined. In addition, mediators related to the activation of the microglia, monocytes, and perivascular macrophages were determined in brain cortices, as well.

Results. In comparison with the control animals, we found increased gene expression of proinflammatory mediators in mice brain cortex in both IMO and LPS groups. In stressed animals, we also showed an increased expression of genes related to the AD neuropathology, as well as positive correlations between genes implicated in AD development and associated neuroinflammation.

Conclusions. Our data indicate that acute exposure to a strong IMO stressor, composed of the combined physical and psychological challenges, induces similar inflammatory and other ADrelated neuropathological changes as the immune LPS treatment. Our data also indicate that cytokines are most likely released from the peripheral immune cells, as we detected myeloid cells activity, without any microglia response. We hypothesize that stress induces innate immune response in the brain that consequently potentiate the expression of genes implicated in the AD-related neuropathology.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Akiyama H Barger S Barnum S Bradt B Bauer J Cole GM Cooper NR Eikelenboom P Emmerling M Fiebich BL Finch CE Frautschy S Griffin WS Hampel H Hull M Landreth G Lue L Mrak R Mackenzie IR McGeer PL O’Banion MK Pachter J Pasinetti G Plata-Salaman C Rogers J Rydel R Shen Y Streit W Strohmeyer R Tooyoma I Van Muiswinkel FL Veerhuis R Walker D Webster S Wegrzyniak B Wenk G Wyss-Coray T. Inflammation and Alzheimer’s disease. Neurobiol Aging 21 383–421 2000.

  • Baglietto-Vargas D Chen Y Suh D Ager RR Rodriguez-Ortiz CJ Medeiros R Myczek K Green KN Baram TZ LaFerla FM. Short-term modern life-like stress exacerbates Abeta-pathology and synapse loss in 3xTg-AD mice. J Neurochem 134 915–926 2015.

  • Biber K Neumann H Inoue K Boddeke HW. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30 596–602 2007.

  • Bidzhekov K Zernecke A Weber C. MCP-1 induces a novel transcription factor with proapoptotic activity. Circ Res 98 1107–1109 2006.

  • Block ML Zecca L Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8 57–69 2007.

  • Catania C Sotiropoulos I Silva R Onofri C Breen KC Sousa N Almeida OF. The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry 14 95–105 2009.

  • Erta M Quintana A Hidalgo J. Interleukin-6 a major cytokine in the central nervous system. Int J Biol Sci 8 1254–1266 2012.

  • Filipcik P Novak P Mravec B Ondicova K Krajciova G Novak M Kvetnansky R. Tau protein phosphorylation in diverse brain areas of normal and CRH deficient mice: up-regulation by stress. Cell Mol Neurobiol 32 837–845 2012.

  • Green KN Billings LM Roozendaal B McGaugh JL LaFerla FM. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 26 9047–9056 2006.

  • Guerriero F Sgarlata C Francis M Maurizi N Faragli A Perna S Rondanelli M Rollone M Ricevuti G. Neuroinflammation immune system and Alzheimer disease: searching for the missing link. Aging Clin Exp Res 29 821–831 2017.

  • Huang NQ Jin H Zhou SY Shi JS Jin F. TLR4 is a link between diabetes and Alzheimer’s disease. Behav Brain Res 316 234–244 2017.

  • Chong Y. Effect of a carboxy-terminal fragment of the Alzheimer’s amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells. Life Sci 61 2323–2333 1997.

  • Krstic D Madhusudan A Doehner J Vogel P Notter T Imhof C Manalastas A Hilfiker M Pfister S Schwerdel C Riether C Meyer U Knuesel I. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation 9 151 2012.

  • Kvetnansky R Mikulaj L. Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology 87 738–743 1970.

  • Lai AY McLaurin J. Clearance of amyloid-beta peptides by microglia and macrophages: the issue of what when and where. Future Neurol 7 165–176 2012.

  • Le MH Weissmiller AM Monte L Lin PH Hexom TC Natera O Wu C Rissman RA. Functional impact of corticotropin-releasing factor exposure on Tau phosphorylation and axon transport. PLoS One 11 e0147250 2016.

  • Liu X Wu Z Hayashi Y Nakanishi H. Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience 216 133–142 2012.

  • Liu YZ Wang YX Jiang CL. Inflammation: The common pathway of stress-related diseases. Front Hum Neurosci 11 316 2017.

  • Marklund N Farrokhnia N Hanell A Vanmechelen E Enblad P Zetterberg H Blennow K Hillered L. Monitoring of beta-amyloid dynamics after human traumatic brain injury. J Neurotrauma 31 42–55 2014.

  • Mecca C Giambanco I Donato R Arcuri C. Microglia and aging: the role of the TREM2–DAP12 and CX3CL1CX3CR1 axes. Int J Mol Sci 19 318 2018.

  • Modur V Li Y Zimmerman GA Prescott SM McIntyre TM. Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor alpha. J Clin Invest 100 2752–2756 1997.

  • Moraes CF Lins TC Carmargos EF Naves JO Pereira RW Nobrega OT. Lessons from genome-wide association studies findings in Alzheimer’s disease. Psychogeriatrics 12 62–73 2012.

  • Muller UC Deller T Korte M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18 281–298 2017.

  • Murakami N Yamaki T Iwamoto Y Sakakibara T Kobori N Fushiki S Ueda S. Experimental brain injury induces expression of amyloid precursor protein which may be related to neuronal loss in the hippocampus. J Neurotrauma 15 993–1003 1998.

  • Nakano Y Furube E Morita S Wanaka A Nakashima T Miyata S. Astrocytic TLR4 expression and LPS-induced nuclear translocation of STAT3 in the sensory circumventricular organs of adult mouse brain. J Neuroimmunol 278 144–158 2015.

  • Novak P Cente M Kosikova N Augustin T Kvetnansky R Novak M Filipcik P. Stress-induced alterations of immune profile in animals suffering by Tau protein-driven neurodegeneration. Cell Mol Neurobiol 38 243–259 2018.

  • Piirainen S Youssef A Song C Kalueff AV Landreth GE Malm T Tian L. Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer’s disease: the emerging role for microglia? Neurosci Biobehav Rev 77 148–164 2017.

  • Ringheim GE Szczepanik AM Petko W Burgher KL Zhu SZ Chao CC. Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. Brain Res Mol Brain Res 55 35–44 1998.

  • Rissman RA Lee KF Vale W Sawchenko PE. Corticotropin-releasing factor receptors differentially regulate stressinduced tau phosphorylation. J Neurosci 27 6552–6562 2007.

  • Romano M Sironi M Toniatti C Polentarutti N Fruscella P Ghezzi P Faggioni R Luini W van Hinsbergh V Sozzani S Bussolino F Poli V Ciliberto G Mantovani A. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6 315–325 1997.

  • Sathyanesan M Haiar JM Watt MJ Newton SS. Restraint stress differentially regulates inflammation and glutamate receptor gene expression in the hippocampus of C57BL/6 and BALB/c mice. Stress 20 197–204 2017.

  • Shen X Chen J Li J Kofler J Herrup K. Neurons in vulnerable regions of the Alzheimer’s disease brain display reduced ATM signaling. eNeuro 3 ENEURO.0124–0115.2016 2016.

  • Schmittgen TD Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3 1101–1108 2008.

  • Small SA Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60 534–542 2008.

  • Spires-Jones TL Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82 756–771 2014.

  • White JD Peterman JL Hardy A Eimerbrink MJ Paulhus KC Thompson MA Chumley MJ Boehm GW. Prior exposure to repeated peripheral LPS injections prevents further accumulation of hippocampal beta-amyloid. Brain Behav Immun 66 e12–e13 2017.

  • Wohleb ES McKim DB Sheridan JF Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci 8 447 2014.

  • Wolf Y Yona S Kim KW Jung S. Microglia seen from the CX3CR1 angle. Front Cell Neurosci 7 26 2013.

  • Yamamoto M Horiba M Buescher JL Huang D Gendelman HE Ransohoff RM Ikezu T. Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am J Pathol 166 1475–1485 2005.

  • Yamamoto M Kiyota T Walsh SM Ikezu T. Kinetic analysis of aggregated amyloid-beta peptide clearance in adult bone-marrow-derived macrophages from APP and CCL2 transgenic mice. J Neuroimmune Pharmacol 2 213–221 2007.

  • Yi MH Zhang E Kang JW Shin YN Byun JY Oh SH Seo JH Lee YH Kim DW. Expression of CD200 in alternative activation of microglia following an excitotoxic lesion in the mouse hippocampus. Brain Res 1481 90–96 2012.

  • Zhang C Kuo CC Moghadam SH Monte L Campbell SN Rice KC Sawchenko PE Masliah E Rissman RA. Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease. Alzheimers Dement 12 527–537 2016.

  • Zhao J O’Connor T Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation 8 150 2011.

  • Zhou L Azfer A Niu J Graham S Choudhury M Adamski FM Younce C Binkley PF Kolattukudy PE. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res 98 1177–1185 2006.

Search
Journal information
Impact Factor


CiteScore 2018: 1.27

SCImago Journal Rank (SJR) 2018: 0.411
Source Normalized Impact per Paper (SNIP) 2018: 0.441

Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 216 216 40
PDF Downloads 144 144 14