Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice

Stephanos Kyrkanides, Ross H Tallents, Jen-Nie H Miller, Mallory E Olschowka, Renee Johnson, Meixiang Yang, John A Olschowka, Sabine M Brouxhon, M Kerry O'Banion, Stephanos Kyrkanides, Ross H Tallents, Jen-Nie H Miller, Mallory E Olschowka, Renee Johnson, Meixiang Yang, John A Olschowka, Sabine M Brouxhon, M Kerry O'Banion

Abstract

Background: The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo.

Methods: We employed the inducible Col1-IL1βXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology.

Results: Induction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1βXAT compound transgenic mouse.

Conclusion: This work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.

Figures

Figure 1
Figure 1
Intra-articular IL-1β over-expression in the adult Col1-IL1βXAT transgenic mouse results in joint pathology with behavioral changes. (A) Intra-articular injection of FIV(gfp) in Col1-IL1βXAT transgenic (Tg) mice (10 μL containing a total of 106 infectious particles) had no effect on IL-1β expression in the joints. In contrast, (B) intra-articular injection of FIV(Cre) in age matched transgenic mice (10 μL containing a total of 106 infectious particles) induced the expression of human IL-1β as detected by immunohistochemistry employing an antibody raised against the mature form of human IL-1β. Moreover, (C) cells infected by FIV(Cre) vector were detected by immunofluorescence (red) utilizing a Texas-Red conjugated antibody raised against the V5 epitope that tagged Cre recombinase in the FIV(Cre) vector (red fluorescence). The reporter gene β-galactosidase (the second ORF in the bicistronic Col1-IL1βXAT transgene) was detected by a polyclonal antibody coupled to Alexa Fluor® 488 (green fluorescence). Therefore, cells infected by FIV(Cre) appear red and cells expressing β-galactosidase appear yellow due to the overlap of green+red. (D) Col1-IL1βXAT transgenic (Tg) mice injected with the control vector FIV(gfp) (10 μL containing a total of 106 infectious particles) did not develop any articular pathology. (E) Conversely, Tg mice injected with FIV(Cre) intra-articularly developed joint pathology, (F) characterized by chondrocyte cloning, erosions and fibrillations. (G) Joint pathology was assessed on histology sections by a 0 - 5 scale. It was found that the mice that received FIV(Cre) intraarticularly (Cre) were characterized by a significant degree of joint pathology. (H) Articular cloning was employed as an additional measure of arthritis, whereby mice with intra-articular FIV(Cre) injection (Cre) were characterized by a significantly higher number of cloned chondrocytes in the articular cartilage. Furthermore, mice with arthritis displayed significantly decreased rotarod activity (I), employed here as a measure of joint dysfunction, as well as (J) significantly increased body grooming, as a measure of discomfort. *p < 0.05; **p < 0.01; ***p < 0.0001; Bar = 100 μM.
Figure 2
Figure 2
Brain inflammation develops secondary to osteoarthritis. (A) Col1-IL1βXAT transgenic mice injected with FIV(gfp) in their joints presented baseline levels of GFAP expression. (B) Col1-IL1βXAT transgenic mice injected with FIV(Cre) in their joints developed increased levels of GFAP expression as evaluated by immunohistochemistry. Similarly, (C) Col1-IL1βXAT transgenic mice injected with FIV(gfp) lacked MHC-II staining in their brain, whereas (D) transgenic mice injected with FIV(Cre) in their joints displayed increased levels of MHC-II expression as evaluated by immunohistochemistry. The GFAP and MHC-II images were obtained from hypothalamic areas. (E) GFAP and MHC-II immunoreactive cells were counted at 2 and 6 months following FIV(gfp) (control) or FIV(Cre) injection in Col1-IL1βXAT transgenic mice. A total of 19 mice was employed in this experiment. (F) Transcript levels for neuroinflammatory genes at 4 months of age were evaluated by real-time qRT-PCR in Col1-IL1βXAT transgenic mice injected at 2 months of age with FIV(gfp), FIV(Cre) or saline. A total of 32 mice was employed in this study. ***p < 0.001; Bar = 50 μm. Mean ± SEM shown.
Figure 3
Figure 3
Arthritis exacerbates and accelerates the development of Aβ plaques in mouse brain. (A) Aβ plaques were not observed in the brain of 4 month old APP/PS1 transgenic mice. Conversely, (B) age and gender matched Col1-IL1βXAT;APP/PS1 mice with osteoarthritis presented Aβ-immunoreactive plaques scattered throughout the brain at 4 months of age. At 8 months of age, (C) APP/PS1 mice displayed Aβ plaque deposits throughout the brain parenchyma. (D) Age and gender matched Col1-IL1βXAT;APP/PS1 mice with osteoarthritis presented many more Aβ plaques. Overall, (E) APP/PS1 mice with arthritis displayed a significantly greater number of Aβ plaques at every time point examined (exacerbation effect), as well as developed Aβ plaque deposits the 4 month time point when no plaques were observed in APP/PS1 mice without arthritis (acceleration effect). (F) There was a modest increase in the number of small Aβ plaque deposits (< 100 μm) after osteoarthritis throughout the brain of Col1-IL1βXAT;APP/PS1 mice with osteoarthritis. The number of large Aβ plaques (> 100 μm), however, significantly increased in the mice with osteoarthritis, especially in the middle and posterior thirds of the brain. A total of 38 mice were included in this experiment: 20 Col1-IL1βXAT;APP/PS1 mice with osteoarthritis and 18 APP/PS1 mice without osteoarthritis. Mean ± SEM shown, ***p < 0.001; Bar = 100 μm.
Figure 4
Figure 4
Osteoarthritis exacerbates neuroinflammation in the presence of Aβ pathology. (A) Four month old APP/PS1 transgenic mice displayed low numbers of GFAP positive astrocytes. (B) The induction of osteoarthritis in the APP/PS1 mouse model resulted in greater number of GFAP+ astrocytes at the 4 month time point. (C) Eight month old APP/PS1 transgenic mice displayed low numbers of GFAP positive astrocytes, whereas (D) animals suffering from osteoarthritis presented with a greater number of reactive astrocytes as evaluated by GFAP immunohistochemistry. Moreover, (E) we observed only a few MHC-II positive cells in the brain of 4 month old APP/PS1 mice, whereas (F) a larger number was noted throughout the brain of Col1-IL1βXAT;APP/PS1 mice with osteoarthritis at the 4 month time point. (G) At eight months of age, we observed only a small number of MHC-II positive cells in APP/PS1 mice, whereas (H) a larger number was noted throughout the brain of Col1-IL1βXAT;APP/PS1 mice with osteoarthritis. (I) MHC-II and GFAP positive cells were quantified in the brains of 8 month wild type (WT), APP/PS1 (AD), Col1-IL1βXAT mice with osteoarthritis (OA), and Col1-IL1βXAT;APP/PS1 mice with osteoarthritis (AD+OA). (J) Transcript levels for neuroinflammatory genes at 8 months of age were evaluated by real-time qRT-PCR in Col1-IL1βXAT;APP/PS1 mice injected with FIV(Cre), FIV(gfp), or saline, as well as wild type mice receiving saline (WT+sal). We observed an upregulation of glial cell activation in the Col1-IL1βXAT;APP/PS1 mice with osteoarthritis. Mean ± SEM shown, ***p < 0.001; Bar = 100 μm.

References

    1. Engelhart MJ. et al.Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study. Arch Neurol. 2004;61:668–672. doi: 10.1001/archneur.61.5.668.
    1. Holmes C. et al.Systemic infection, interleukin-1β and cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003;74:788–789. doi: 10.1136/jnnp.74.6.788.
    1. Tan ZS. et al.Inflammatory markers and the risk of Alzheimer's disease: the Framingham study. Neurol. 2007;70:1222–1223.
    1. Bermejo P. et al.Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett. 2007;117:198–202.
    1. Bonotis K. et al.Systemic immune aberrations in Alzheimer's disease patients. J Immunol. 2008;193:183–187.
    1. Holmes C. et al.Systemic inflammation and disease progression in Alzheimer disease. Neurol. 2009;73:768–774. doi: 10.1212/WNL.0b013e3181b6bb95.
    1. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992;22:396–402. doi: 10.1111/j.1365-2362.1992.tb01480.x.
    1. Griffin WS, Nicoll JA, Grimaldi LM, Sheng JG, Mrak RE. The pervasiveness of interleukin-1 in alzheimer pathogenesis: a role for specific polymorphisms in disease risk. Exp Gerotontol. 2000;35:481–487. doi: 10.1016/S0531-5565(00)00110-8.
    1. Cunningham C. et al.Comparison of inflammatory and acute-phase responses in the brain and peripheral organs of the ME7 model of prior disease. J Virol. 2005;79:5174–5184. doi: 10.1128/JVI.79.8.5174-5184.2005.
    1. Cunningham C. et al.Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psych. 2009;65:304–312. doi: 10.1016/j.biopsych.2008.07.024.
    1. Lee JW. et al.Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflam. 2008;5:37–37. doi: 10.1186/1742-2094-5-37.
    1. Sly LM. et al.Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer's disease. Brain Res Bull. 2001;56:581–588. doi: 10.1016/S0361-9230(01)00730-4.
    1. Qiao X, Cummins DJ, Paul SM. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci. 2001;14:474–482. doi: 10.1046/j.0953-816x.2001.01666.x.
    1. Sheng JG, Price DL, Koliatsos VE. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis. 2003;14:133–145. doi: 10.1016/S0969-9961(03)00069-X.
    1. DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan. Intrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice. Neurobiol Aging. 2001;22:1007–1012. doi: 10.1016/S0197-4580(01)00292-5.
    1. Quinn J. et al.Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer disease. J Neuroimmunol. 2003;137:32–41. doi: 10.1016/S0165-5728(03)00037-7.
    1. Herber DL. et al.Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice. Exp Neurol. 2004;190:245–253. doi: 10.1016/j.expneurol.2004.07.007.
    1. Chakrabarty P. et al.Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB. 2004;24:548–559.
    1. Shaftel SS. et al.Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest. 2007;117:1595–1604. doi: 10.1172/JCI31450.
    1. Staite ND. et al.Induction of an acute erosive monarticular arthritis in mice by interleukin-1 and methylated bovine serum albumin. Arthr Rheum. 1990;33:253–260. doi: 10.1002/art.1780330215.
    1. Ghivizzani SC. et al.Constitutive intra-articular expression of human IL-1β following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis. J Immunol. 1997;159:3604–12.
    1. Lawlor KE. et al.Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis. Arthr Rheum. 2001;44:442–50. doi: 10.1002/1529-0131(200102)44:2<442::AID-ANR63>;2-M.
    1. Lai Y-C. et al.Intra-articular induction of chronic IL-1β expression in the adult mouse results in an osteoarthritis-like phenotype accompanied by pain. Arthr Rheum. 2006;54:1184–97. doi: 10.1002/art.21771.
    1. Kyrkanides S. et al.Intra-articular μ-opioid receptor induction ameliorates arthritic pain and joint pathology. Arthr Rheum. 2007;56:2038–48. doi: 10.1002/art.22635.
    1. Fiorentino PM. et al.Spinal IL-1β in arthritis and joint pain. Arthr Rheum. 2008;58:3100–3109. doi: 10.1002/art.23866.
    1. Jankowsky JL. et al.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. 2004;13:159–170.
    1. Combrinck MI, Perry VH, Cunningham C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neurosci. 2002;112:7–11. doi: 10.1016/S0306-4522(02)00030-1.
    1. Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci. 2005;25:8843–53. doi: 10.1523/JNEUROSCI.2868-05.2005.
    1. McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in Alzheimer's disease. Can J Neurol Sci. 1989;16:516–527.
    1. Rogers J. et al.Clinical trial of indomethacin in Alzheimer's disease. Neurol. 1993;43:1609–1611.
    1. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurol. 1996;47:425–432.
    1. Aisen PS. et al.A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative study. Neurol. 2000;54:588–593.
    1. Aisen. et al.Effects of rofecoxib or naproxen versus placebo on Alzheimer Disease progression: a randomized controlled trial. JAMA. 2003;289:2819–2826. doi: 10.1001/jama.289.21.2819.
    1. Group AR. et al.Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurol. 2007;68:1800–1808.
    1. Thal lJ. et al.A randomized, double blind study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacol. 2005;30:1204–1215. doi: 10.1038/sj.npp.1300690.
    1. Lyketsos CG. et al.Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. ADAPT Research Group. Neurol. 2007;68:1800–1808.
    1. Choi J-K. et al.Anti-inflammatory treatment in AD mice protects against neuronal pathology. Exp Neurol. 2010;223:377–384. doi: 10.1016/j.expneurol.2009.07.032.
    1. Weggen S. et al.A subset of NSAIDs lowers amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414:212–16. doi: 10.1038/35102591.
    1. Shaftel SS. et al.Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci. 2007;27:9301–9. doi: 10.1523/JNEUROSCI.1418-07.2007.
    1. Houssein MR, Fathi NA, El-Din AME, Hassan HI, Abdullah F, Al-Hakeem E, Backer EA. Alterations of the CD4+, CD8+ T Cell Subsets, Interleukins-1β, IL-10, IL-17, Tumor Necrosis Factor-α and Soluble Intercellular Adhesion Molecule-1 in Rheumatoid Arthritis and Osteoarthritis: Preliminary Observations. Pathol Oncol Res. 2008;14:321–8. doi: 10.1007/s12253-008-9016-1.
    1. Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: Effects on cognitive processes. Neuroimmunomodul. 2002;10:319–27. doi: 10.1159/000071472.
    1. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Trends Neurosci. 2002;25:154–159. doi: 10.1016/S0166-2236(00)02088-9.
    1. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflam. 2005;2:22. doi: 10.1186/1742-2094-2-22.
    1. Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, Shah GN, Price TO, Fleegal-Demotta MA, Butterfiled DA, Banks WA. Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease. Brain Behav Immun. 2009;23:507–17. doi: 10.1016/j.bbi.2009.01.017.
    1. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008;28:8354–60. doi: 10.1523/JNEUROSCI.0616-08.2008.
    1. Adlard ePA, Perreau VM, Pop V, Cotman CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci. 2005;25:4217–21. doi: 10.1523/JNEUROSCI.0496-05.2005.
    1. Ke H-C, Huang H-J, Liang K-C, Hsieh HM. Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise. Brain Res. 2011;1403:1–11.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner