Skip to main content
SpringerLink
Log in

Inflammation and Alzheimer’s disease

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by extracellular deposition of a specific protein, beta-amyloid peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. Although the pathophysiologic mechanism is not fully established, inflammation appears to be involved. Neuroinflammation has been known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular. Numerous studies show the presence of a number of markers of inflammation in the AD brain: elevated inflammatory cytokines and chemokines, and accumulation of activated microglia in the damaged regions. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between neuroinflammation and AD pathogenesis. The aim of this review is (1) to assess the association between neuroinflammation and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abraham, C. R., Reactive astrocytes and alpha1-antichymotrypsin in Alzheimer’s disease. Neurobiol. Aging, 22, 931–936 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Aisen, P. S., Schmeidler, J., and Pasinetti, G. M., Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology, 58, 1050–1054 (2002).

    CAS  PubMed  Google Scholar 

  • Aisen, P. S., Schafer, K. A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K. L., Farlow, M. R., Jin, S., Thomas, R. G., and Thal, L. J., Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA, 289, 2819–2826 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Aisen, P. S., Thal, L. J., Ferris, S. H., Assaid, C., Nessly, M. L., Giuliani, M. J., Lines, C. R., Norman, B. A., and Potter, W. Z., Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial. Curr. Alzheimer Res., 5, 73–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Akiyama, H., Arai, T., Kondo, H., Tanno, E., Haga, C., and Ikeda, K., Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis. Assoc. Disord., 14Suppl 1, S47–S53 (2000).

    CAS  PubMed  Google Scholar 

  • Alafuzoff, I., Overmyer, M., Helisalmi, S., and Soininen, H., Lower counts of astroglia and activated microglia in patients with Alzheimer’s disease with regular use of nonsteroidal anti-inflammatory drugs. J. Alzheimers Dis., 2, 37–46 (2000).

    CAS  PubMed  Google Scholar 

  • Anthony, J. C., Breitner, J. C., Zandi, P. P., Meyer, M. R., Jurasova, I., Norton, M. C., and Stone, S. V., Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology, 54, 2066–2071 (2000).

    CAS  PubMed  Google Scholar 

  • Arce, M. P., Rodriguez-Franco, M. I., Gonzalez-Munoz, G. C., Perez, C., Lopez, B., Villarroya, M., Lopez, M. G., Garcia, A. G., and Conde, S., Neuroprotective and cholinergic properties of multifunctional glutamic acid derivatives for the treatment of Alzheimer’s disease. J. Med. Chem., 52, 7249–7257 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Atwood, C. S., Obrenovich, M. E., Liu, T., Chan, H., Perry, G., Smith, M. A., and Martins, R. N., Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res. Brain Res. Rev., 43, 1–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Ballatore, C., Lee, V. M., and Trojanowski, J. Q., Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci., 8, 663–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Bazan, N. G., COX-2 as a multifunctional neuronal modulator. Nat. Med., 7, 414–415 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Bentham, P., Gray, R., Sellwood, E., Hills, R., Crome, P., and Raftery, J., Aspirin in Alzheimer’s disease (AD2000): a randomised open-label trial. Lancet Neurol., 7, 41–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Bernardo, A. and Minghetti, L., PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr. Pharm. Des., 12, 93–109 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Biber, K., Vinet, J., and Boddeke, H. W., Neuron-microglia signaling: chemokines as versatile messengers. J. Neuroimmunol., 198, 69–74 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Birks, J., Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst. Rev., CD005593 (2006).

  • Blass, D. M. and Rabins, P. V., In the clinic. Dementia. Ann. Intern. Med., 148, ITC4-1–ITC4-16 (2008).

    Google Scholar 

  • Blennow, K., De Leon, M. J., and Zetterberg, H., Alzheimer’s disease. Lancet, 368, 387–403 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Boissonneault, V., Filali, M., Lessard, M., Relton, J., Wong, G., and Rivest, S., Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer’s disease. Brain, 132, 1078–1092 (2009).

    Article  PubMed  Google Scholar 

  • Cai, X. D., Golde, T. E., and Younkin, S. G., Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science, 259, 514–516 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Cakala, M., Malik, A. R., and Strosznajder, J. B., Inhibitor of cyclooxygenase-2 protects against amyloid beta peptide-evoked memory impairment in mice. Pharmacol. Rep., 59, 164–172 (2007).

    CAS  PubMed  Google Scholar 

  • Camacho, I. E., Serneels, L., Spittaels, K., Merchiers, P., Dominguez, D., and De Strooper, B., Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J. Neurosci., 24, 10908–10917 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Chao, C. C., Hu, S., Sheng, W. S., Bu, D., Bukrinsky, M. I., and Peterson, P. K., Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism. Glia, 16, 276–284 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Cheng, S. Y. and Trombetta, L. D., The induction of amyloid precursor protein and alpha-synuclein in rat hippocampal astrocytes by diethyldithiocarbamate and copper with or without glutathione. Toxicol. Lett., 146, 139–149 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Chiu, C. C., Su, K. P., Cheng, T. C., Liu, H. C., Chang, C. J., Dewey, M. E., Stewart, R., and Huang, S. Y., The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog. Neuropsychopharmacol. Biol. Psychiatry, 32, 1538–1544 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Selkoe, D. J., Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature, 360, 672–674 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Citron, M., Vigo-Pelfrey, C., Teplow, D. B., Miller, C., Schenk, D., Johnston, J., Winblad, B., Venizelos, N., Lannfelt, L., and Selkoe, D. J., Excessive production of amyloid betaprotein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc. Natl. Acad. Sci. U.S.A., 91, 11993–11997 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Cole, G. M., Teter, B., and Frautschy, S. A., Neuroprotective effects of curcumin. Adv. Exp. Med. Biol., 595, 197–212 (2007).

    Article  PubMed  Google Scholar 

  • Colton, C. A., Mott, R. T., Sharpe, H., Xu, Q., Van Nostrand, W. E., and Vitek, M. P., Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation, 3, 27 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B., and Landreth, G. E., Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPAR-gamma agonists. J. Neurosci., 20, 558–567 (2000).

    CAS  PubMed  Google Scholar 

  • Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., Beal, M. F., and Wallace, D. C., Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat. Genet., 2, 324–329 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Couzin, J., Clinical trials. Halt of Celebrex study threatens drug’s future, other trials. Science, 306, 2170 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Cutler, R. G., Kelly, J., Storie, K., Pedersen, W. A., Tammara, A., Hatanpaa, K., Troncoso, J. C., and Mattson, M. P., Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A., 101, 2070–2075 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Czirr, E. and Weggen, S., Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds. Neurodegener. Dis., 3, 298–304 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Das, S. and Basu, A., Inflammation: a new candidate in modulating adult neurogenesis. J. Neurosci. Res., 86, 1199–1208 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Davis, S. and Laroche, S., What can rodent models tell us about cognitive decline in Alzheimer’s disease? Mol. Neurobiol., 27, 249–276 (2003).

    Article  CAS  PubMed  Google Scholar 

  • De Haas, A. H., Van Weering, H. R., De Jong, E. K., Boddeke, H. W., and Biber, K. P., Neuronal chemokines: versatile messengers in central nervous system cell interaction. Mol. Neurobiol., 36, 137–151 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Dickson, D. W., The pathogenesis of senile plaques. J. Neuropathol. Exp. Neurol., 56, 321–339 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Dill, J., Patel, A. R., Yang, X. L., Bachoo, R., Powell, C. M., and Li, S., A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. J. Neurosci., 30, 963–972 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Dyall, S. C., Michael, G. J., and Michael-Titus, A. T., Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. J. Neurosci. Res., 88, 2091–2102 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Dzenko, K. A., Weltzien, R. B., and Pachter, J. S., Suppression of A beta-induced monocyte neurotoxicity by antiinflammatory compounds. J. Neuroimmunol., 80, 6–12 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Eikelenboom, P., Bate, C., Van Gool, W. A., Hoozemans, J. J., Rozemuller, J. M., Veerhuis, R., and Williams, A., Neuroinflammation in Alzheimer’s disease and prion disease. Glia, 40, 232–239 (2002).

    Article  CAS  PubMed  Google Scholar 

  • El Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., and Loike, J. D., Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature, 382, 716–719 (1996).

    Article  PubMed  Google Scholar 

  • Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., and Golde, T. E., NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J. Clin. Invest., 112, 440–449 (2003).

    CAS  PubMed  Google Scholar 

  • Ferri, C. P., Sousa, R., Albanese, E., Ribeiro, W. S., and Honyashiki, M., World Alzheimer Report 2009 — Executive Summary. In Prince, M. and Jackson, J. (Eds.). Alzheimer’s Disease International, London, pp. 1–22, (2009).

    Google Scholar 

  • Frederiksen, K., Thorpe, A., Richards, S. J., Waters, J., Dunnett, S. B., and Sandberg, B. E., Immortalized neural cells from trisomy 16 mice as models for Alzheimer’s disease. Ann. N. Y. Acad. Sci., 777, 415–420 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Freund-Levi, Y., Eriksdotter-Jonhagen, M., Cederholm, T., Basun, H., Faxen-Irving, G., Garlind, A., Vedin, I., Vessby, B., Wahlund, L. O., and Palmblad, J., Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol., 63, 1402–1408 (2006).

    Article  PubMed  Google Scholar 

  • Friedman, W. J., Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia. Exp. Neurol., 168, 23–31 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Fu, Q., Hue, J., and Li, S., Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. J. Neurosci., 27, 4154–4164 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Gala, M., Sun, R., and Yang, V. W., Inhibition of cell transformation by sulindac sulfide is confined to specific oncogenic pathways. Cancer Lett., 175, 89–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Alloza, M., Borrelli, L. A., Rozkalne, A., Hyman, B. T., and Bacskai, B. J., Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J. Neurochem., 102, 1095–1104 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Giaccone, G., Tagliavini, F., Linoli, G., Bouras, C., Frigerio, L., Frangione, B., and Bugiani, O., Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci. Lett., 97, 232–238 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Goedert, M., Klug, A., and Crowther, R. A., Tau protein, the paired helical filament and Alzheimer’s disease. J. Alzheimers Dis., 9, 195–207 (2006).

    CAS  PubMed  Google Scholar 

  • Gomez-Isla, T., Blesa, R., Boada, M., Clarimon, J., Del Ser, T., Domenech, G., Ferro, J. M., Gomez-Anson, B., Manubens, J. M., Martinez-Lage, J. M., Munoz, D., Pena-Casanova, J., and Torres, F., A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis. Assoc. Disord., 22, 21–29 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Gottschall, P. E., beta-Amyloid induction of gelatinase B secretion in cultured microglia: inhibition by dexamethasone and indomethacin. Neuroreport, 7, 3077–3080 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Guglielmotto, M., Giliberto, L., Tamagno, E., and Tabaton, M., Oxidative stress mediates the pathogenic effect of different Alzheimer’s disease risk factors. Front. Aging Neurosci., 2, 3 (2010).

    PubMed  Google Scholar 

  • Haass, C. and De Strooper, B., The presenilins in Alzheimer’s disease—proteolysis holds the key. Science, 286, 916–919 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Haass, C. and Selkoe, D. J., Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat. Rev. Mol. Cell Biol., 8, 101–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Harman, D., Free radical theory of aging. Mutat. Res., 275, 257–266 (1992).

    CAS  PubMed  Google Scholar 

  • Hauss-Wegrzyniak, B., Dobrzanski, P., Stoehr, J. D., and Wenk, G. L., Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res., 780, 294–303 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Hauss-Wegrzyniak, B., Galons, J. P., and Wenk, G. L., Quantitative volumetric analyses of brain magnetic resonance imaging from rat with chronic neuroinflammation. Exp. Neurol., 165, 347–354 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Hauss-Wegrzyniak, B., Lynch, M. A., Vraniak, P. D., and Wenk, G. L., Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp. Neurol., 176, 336–341 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Heneka, M. T., Wiesinger, H., Dumitrescu-Ozimek, L., Riederer, P., Feinstein, D. L., and Klockgether, T., Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J. Neuropathol. Exp. Neurol., 60, 906–916 (2001).

    CAS  PubMed  Google Scholar 

  • Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Hanke, A., Dewachter, I., Kuiperi, C., O’Banion, K., Klockgether, T., Van Leuven, F., and Landreth, G. E., Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain, 128, 1442–1453 (2005).

    Article  PubMed  Google Scholar 

  • Herrmann, C., Block, C., Geisen, C., Haas, K., Weber, C., Winde, G., Moroy, T., and Muller, O., Sulindac sulfide inhibits Ras signaling. Oncogene, 17, 1769–1776 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Hickman, S. E., Allison, E. K., and El Khoury, J., Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci., 28, 8354–8360 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Hoshino, T., Namba, T., Takehara, M., Nakaya, T., Sugimoto, Y., Araki, W., Narumiya, S., Suzuki, T., and Mizushima, T., Prostaglandin E2 stimulates the production of amyloidbeta peptides through internalization of the EP4 receptor. J. Biol. Chem., 284, 18493–18502 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Hu, J., Akama, K. T., Krafft, G. A., Chromy, B. A., and Van Eldik, L. J., Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res., 785, 195–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Hwang, D. Y., Chae, K. R., Kang, T. S., Hwang, J. H., Lim, C. H., Kang, H. K., Goo, J. S., Lee, M. R., Lim, H. J., Min, S. H., Cho, J. Y., Hong, J. T., Song, C. W., Paik, S. G., Cho, J. S., and Kim, Y. K., Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB J., 16, 805–813 (2002).

    Article  CAS  PubMed  Google Scholar 

  • In T’ Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., Van Duijn, C. M., Stijnen, T., Breteler, M. M., and Stricker, B. H., Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med., 345, 1515–1521 (2001).

    Article  Google Scholar 

  • Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C. X., Khatoon, S., Li, B., Liu, F., Rahman, A., Tanimukai, H., and Grundke-Iqbal, I., Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta, 1739, 198–210 (2005).

    CAS  PubMed  Google Scholar 

  • Iqbal, K., Liu, F., Gong, C. X., Alonso Adel, C., and Grundke-Iqbal, I., Mechanisms of tau-induced neurodegeneration. Acta Neuropathol., 118, 53–69 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Jacob, A., Wu, R., Zhou, M., and Wang, P., Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-gamma Activation. PPAR Res., 2007, 89369 (2007).

    PubMed  Google Scholar 

  • Jaradat, M. S., Wongsud, B., Phornchirasilp, S., Rangwala, S. M., Shams, G., Sutton, M., Romstedt, K. J., Noonan, D. J., and Feller, D. R., Activation of peroxisome proliferators-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. Biochem. Pharmacol., 62, 1587–1595 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Jiang, C., Ting, A. T., and Seed, B., PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature, 391, 82–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Jiang, Q., Heneka, M., and Landreth, G. E., The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer’s disease: therapeutic implications. CNS Drugs, 22, 1–14 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., and Vitorica, J., Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J. Neurosci., 28, 11650–11661 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Johnstone, M., Gearing, A. J., and Miller, K. M., A central role for astrocytes in the inflammatory response to betaamyloid; chemokines, cytokines and reactive oxygen species are produced. J. Neuroimmunol., 93, 182–193 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Kashfi, K. and Rigas, B., Non-COX-2 targets and cancer: expanding the molecular target repertoire of chemoprevention. Biochem. Pharmacol., 70, 969–986 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Kern, A. and Behl, C., The unsolved relationship of brain aging and late-onset Alzheimer disease. Biochim. Biophys. Acta, 1790, 1124–1132 (2009).

    CAS  PubMed  Google Scholar 

  • Kim, T. I., Lee, Y. K., Park, S. G., Choi, I. S., Ban, J. O., Park, H. K., Nam, S. Y., Yun, Y. W., Han, S. B., Oh, K. W., and Hong, J. T., l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic. Biol. Med., 47, 1601–1610 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Kitazawa, M., Yamasaki, T. R., and Laferla, F. M., Microglia as a potential bridge between the amyloid beta-peptide and tau. Ann. N. Y. Acad. Sci., 1035, 85–103 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Klegeris, A., Walker, D. G., and McGeer, P. L., Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs). Neuropharmacology, 38, 1017–1025 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Klein, R. L., Dayton, R. D., Diaczynsky, C. G., and Wang, D. B., Pronounced microgliosis and neurodegeneration in aged rats after tau gene transfer. Neurobiol. Aging, (2009).

  • Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R., and Paul, S. M., Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med., 10, 719–726 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Kotilinek, L. A., Westerman, M. A., Wang, Q., Panizzon, K., Lim, G. P., Simonyi, A., Lesne, S., Falinska, A., Younkin, L. H., Younkin, S. G., Rowan, M., Cleary, J., Wallis, R. A., Sun, G. Y., Cole, G., Frautschy, S., Anwyl, R., and Ashe, K. H., Cyclooxygenase-2 inhibition improves amyloidbeta-mediated suppression of memory and synaptic plasticity. Brain, 131, 651–664 (2008).

    Article  PubMed  Google Scholar 

  • Kukar, T., Murphy, M. P., Eriksen, J. L., Sagi, S. A., Weggen, S., Smith, T. E., Ladd, T., Khan, M. A., Kache, R., Beard, J., Dodson, M., Merit, S., Ozols, V. V., Anastasiadis, P. Z., Das, P., Fauq, A., Koo, E. H., and Golde, T. E., Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat. Med., 11, 545–550 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Kukar, T. L., Ladd, T. B., Bann, M. A., Fraering, P. C., Narlawar, R., Maharvi, G. M., Healy, B., Chapman, R., Welzel, A. T., Price, R. W., Moore, B., Rangachari, V., Cusack, B., Eriksen, J., Jansen-West, K., Verbeeck, C., Yager, D., Eckman, C., Ye, W., Sagi, S., Cottrell, B. A., Torpey, J., Rosenberry, T. L., Fauq, A., Wolfe, M. S., Schmidt, B., Walsh, D. M., Koo, E. H., and Golde, T. E., Substrate-targeting gamma-secretase modulators. Nature, 453, 925–929 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Kurt, M. A., Davies, D. C., and Kidd, M., beta-Amyloid immunoreactivity in astrocytes in Alzheimer’s disease brain biopsies: an electron microscope study. Exp. Neurol., 158, 221–228 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Landreth, G., Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer’s disease. Curr. Alzheimer Res., 4, 159–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Landreth, G. E. and Heneka, M. T., Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer’s disease. Neurobiol. Aging, 22, 937–944 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Lee, J. W., Lee, Y. K., Yuk, D. Y., Choi, D. Y., Ban, S. B., Oh, K. W., and Hong, J. T., Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J. Neuroinflammation, 5, 37 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Lee, J. W., Lee, Y. K., Ban, J. O., Ha, T. Y., Yun, Y. P., Han, S. B., Oh, K. W., and Hong, J. T., Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice. J. Nutr., 139, 1987–1993 (2009a).

    Article  CAS  PubMed  Google Scholar 

  • Lee, S. Y., Lee, J. W., Lee, H., Yoo, H. S., Yun, Y. P., Oh, K. W., Ha, T. Y., and Hong, J. T., Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. Brain Res. Mol. Brain Res., 140, 45–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Lee, S. Y., Hwang, D. Y., Kim, Y. K., Lee, J. W., Shin, I. C., Oh, K. W., Lee, M. K., Lim, J. S., Yoon, D. Y., Hwang, S. J., and Hong, J. T., PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release. FASEB J., 20, 151–153 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y. K., Yuk, D. Y., Lee, J. W., Lee, S. Y., Ha, T. Y., Oh, K. W., Yun, Y. P., and Hong, J. T., (-)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency. Brain Res., 1250, 164–174 (2009b).

    Article  CAS  PubMed  Google Scholar 

  • Lehmann, J. M., Lenhard, J. M., Oliver, B. B., Ringold, G. M., and Kliewer, S. A., Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem., 272, 3406–3410 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Li, H., Ruan, X. Z., Powis, S. H., Fernando, R., Mon, W. Y., Wheeler, D. C., Moorhead, J. F., and Varghese, Z., EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int., 67, 867–874 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Li, Y., Barger, S. W., Liu, L., Mrak, R. E., and Griffin, W. S., S100beta induction of the proinflammatory cytokine interleukin-6 in neurons. J. Neurochem., 74, 143–150 (2000).

    CAS  PubMed  Google Scholar 

  • Lieberman, J. A., Javitch, J. A., and Moore, H., Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am. J. Psychiatry, 165, 931–936 (2008).

    Article  PubMed  Google Scholar 

  • Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., Tran, T., Ubeda, O., Ashe, K. H., Frautschy, S. A., and Cole, G. M., Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci., 20, 5709–5714 (2000).

    CAS  PubMed  Google Scholar 

  • Lin, J. and Chen, A., Activation of peroxisome proliferators-activated receptor-gamma by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells. Lab. Invest., 88, 529–540 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Lleo, A., Galea, E., and Sastre, M., Molecular targets of nonsteroidal anti-inflammatory drugs in neurodegenerative diseases. Cell. Mol. Life Sci., 64, 1403–1418 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Lossinsky, A. S. and Shivers, R. R., Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. Histol. Histopathol., 19, 535–564 (2004).

    CAS  PubMed  Google Scholar 

  • Lucin, K. M. and Wyss-Coray, T., Immune activation in brain aging and neurodegeneration: too much or too little? Neuron, 64, 110–122 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Lue, L. F., Walker, D. G., Brachova, L., Beach, T. G., Rogers, J., Schmidt, A. M., Stern, D. M., and Yan, S. D., Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp. Neurol., 171, 29–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Lyketsos, C. G., Breitner, J. C., Green, R. C., Martin, B. K., Meinert, C., Piantadosi, S., and Sabbagh, M., Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology, 68, 1800–1808 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Mann, D. M. and Esiri, M. M., The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J. Neurol. Sci., 89, 169–179 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Maragakis, N. J. and Rothstein, J. D., Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat. Clin. Pract. Neurol., 2, 679–689 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Maramband, P. Chevallier, N., Ancolio, K., and Checler, F., Post-transcriptional contribution of a cAMP-dependent pathway to the formation of α- and β/γ-secretases-derived products of βAPP maturation in human cells expressing wild-type and Swedish mutated βAPP. Mol. Med., 4, 715–723 (1998).

    Google Scholar 

  • Mattson, M. P., Maudsley, S., and Martin, B., A neural signaling triumvirate that influences ageing and agerelated disease: insulin/IGF-1, BDNF and serotonin. Ageing Res. Rev., 3, 445–464 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Mayeux, R., Ottman, R., Maestre, G., Ngai, C., Tang, M. X., Ginsberg, H., Chun, M., Tycko, B., and Shelanski, M., Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer’s disease. Neurology, 45, 555–557 (1995).

    CAS  PubMed  Google Scholar 

  • McGeer, E. G. and McGeer, P. L., Inflammatory processes in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry, 27, 741–749 (2003).

    Article  CAS  PubMed  Google Scholar 

  • McGeer, P. L. and Rogers, J., Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology, 42, 447–449 (1992).

    CAS  PubMed  Google Scholar 

  • McGeer, P. L. and McGeer, E. G., The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Brain Res. Rev., 21, 195–218 (1995).

    Article  CAS  PubMed  Google Scholar 

  • McGeer, P. L. and McGeer, E. G., Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging, 22, 799–809 (2001).

    Article  CAS  PubMed  Google Scholar 

  • McNaull, B. B., Todd, S., McGuinness, B., and Passmore, A. P., Inflammation and anti-inflammatory strategies for Alzheimer’s disease—a mini-review. Gerontology, 56, 3–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., De Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., and Hyman, B. T., Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature, 451, 720–724 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Moore, A. H., Olschowka, J. A., Williams, J. P., Okunieff, P., and O’Banion, M. K., Regulation of prostaglandin E2 synthesis after brain irradiation. Int. J. Radiat. Oncol. Biol. Phys., 62, 267–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Mori, T., Koyama, N., Arendash, G. W., Horikoshi-Sakuraba, Y., Tan, J., and Town, T., Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia, 58, 300–314 (2009).

    Google Scholar 

  • Morihara, T., Chu, T., Ubeda, O., Beech, W., and Cole, G. M., Selective inhibition of Abeta42 production by NSAID Renantiomers. J. Neurochem., 83, 1009–1012 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Mott, R. T., Ait-Ghezala, G., Town, T., Mori, T., Vendrame, M., Zeng, J., Ehrhart, J., Mullan, M., and Tan, J., Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia, 46, 369–379 (2004).

    Article  PubMed  Google Scholar 

  • Mrak, R. E. and Griffinbc, W. S., The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s disease. Neurobiol. Aging, 22, 915–922 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Murakami, K., Irie, K., Ohigashi, H., Hara, H., Nagao, M., Shimizu, T., and Shirasawa, T., Formation and stabilization model of the 42-mer Abeta radical: implications for the long-lasting oxidative stress in Alzheimer’s disease. J. Am. Chem. Soc., 127, 15168–15174 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Murray, I. V., Liu, L., Komatsu, H., Uryu, K., Xiao, G., Lawson, J. A., and Axelsen, P. H., Membrane-mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid beta proteins. J. Biol. Chem., 282, 9335–9345 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Nagele, R. G., D’Andrea, M. R., Lee, H., Venkataraman, V., and Wang, H. Y., Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res., 971, 197–209 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Netland, E. E., Newton, J. L., Majocha, R. E., and Tate, B. A., Indomethacin reverses the microglial response to amyloid beta-protein. Neurobiol. Aging, 19, 201–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Neumann, K. F., Rojo, L., Navarrete, L. P., Farias, G., Reyes, P., and Maccioni, R. B., Insulin resistance and Alzheimer’s disease: molecular links & clinical implications. Curr. Alzheimer Res., 5, 438–447 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Nilsson, L. N., Das, S., and Potter, H., Effect of cytokines, dexamethasone and the A/T-signal peptide polymorphism on the expression of alpha(1)-antichymotrypsin in astrocytes: significance for Alzheimer’s disease. Neurochem. Int., 39, 361–370 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Nunan, J. and Small, D. H., Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett., 483, 6–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., Jones, P. K., Ghanbari, H., Wataya, T., Shimohama, S., Chiba, S., Atwood, C. S., Petersen, R. B., and Smith, M. A., Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol., 60, 759–767 (2001).

    CAS  PubMed  Google Scholar 

  • Pasinetti, G. M. and Aisen, P. S., Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease brain. Neuroscience, 87, 319–324 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Patil, S., Sheng, L., Masserang, A., and Chan, C., Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons. Neurosci. Lett., 406, 55–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Pavlov, V. A. and Tracey, K. J., The cholinergic anti-inflammatory pathway. Brain Behav. Immun., 19, 493–499 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Pedersen, W. A., McMillan, P. J., Kulstad, J. J., Leverenz, J. B., Craft, S., and Haynatzki, G. R., Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp. Neurol., 199, 265–273 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Perry, G., Nunomura, A., Hirai, K., Takeda, A., Aliev, G., and Smith, M. A., Oxidative damage in Alzheimer’s disease: the metabolic dimension. Int. J. Dev. Neurosci., 18, 417–421 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Pratico, D. and Trojanowski, J. Q., Inflammatory hypotheses: novel mechanisms of Alzheimer’s neurodegeneration and new therapeutic targets? Neurobiol. Aging, 21, 441–445; discussion 451–453 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Priller, C., Bauer, T., Mitteregger, G., Krebs, B., Kretzschmar, H. A., and Herms, J., Synapse formation and function is modulated by the amyloid precursor protein. J. Neurosci., 26, 7212–7221 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Prosperi, C., Scali, C., Barba, M., Bellucci, A., Giovannini, M. G., Pepeu, G., and Casamenti, F., Comparison between flurbiprofen and its nitric oxide-releasing derivatives HCT-1026 and NCX-2216 on Abeta(1–42)-induced brain inflammation and neuronal damage in the rat. Int. J. Immunopathol. Pharmacol., 17, 317–330 (2004).

    CAS  PubMed  Google Scholar 

  • Qaseem, A., Snow, V., Cross, J. T., Jr., Forciea, M. A., Hopkins, R., Jr., Shekelle, P., Adelman, A., Mehr, D., Schellhase, K., Campos-Outcalt, D., Santaguida, P., and Owens, D. K., Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann. Intern. Med., 148, 370–378 (2008).

    PubMed  Google Scholar 

  • Raina, P., Santaguida, P., Ismaila, A., Patterson, C., Cowan, D., Levine, M., Booker, L., and Oremus, M., Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann. Intern. Med., 148, 379–397 (2008).

    PubMed  Google Scholar 

  • Raschetti, R., Albanese, E., Vanacore, N., and Maggini, M., Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med., 4, e338 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Reid, G., Wielinga, P., Zelcer, N., Van der heijden, I., Kuil, A., De Haas, M., Wijnholds, J., and Borst, P., The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc. Natl. Acad. Sci. U.S.A., 100, 9244–9249 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Reines, S. A., Block, G. A., Morris, J. C., Liu, G., Nessly, M. L., Lines, C. R., Norman, B. A., and Baranak, C. C., Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology, 62, 66–71 (2004).

    CAS  PubMed  Google Scholar 

  • Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., and Brandt, J., Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology, 45, 51–55 (1995).

    CAS  PubMed  Google Scholar 

  • Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., and Glass, C. K., The peroxisome proliferator-activated receptorgamma is a negative regulator of macrophage activation. Nature, 391, 79–82 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Rinaldi, P., Polidori, M. C., Metastasio, A., Mariani, E., Mattioli, P., Cherubini, A., Catani, M., Cecchetti, R., Senin, U., and Mecocci, P., Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol. Aging, 24, 915–919 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Risner, M. E., Saunders, A. M., Altman, J. F., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., and Roses, A. D., Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J., 6, 246–254 (2006).

    CAS  PubMed  Google Scholar 

  • Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L., Kaszniak, A. W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., and Kogan, F., Clinical trial of indomethacin in Alzheimer’s disease. Neurology, 43, 1609–1611 (1993).

    CAS  PubMed  Google Scholar 

  • Rogers, J. and Lue, L. F., Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer’s disease. Neurochem. Int., 39, 333–340 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Rojo, L. E., Fernandez, J. A., Maccioni, A. A., Jimenez, J. M., and Maccioni, R. B., Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch. Med. Res., 39, 1–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Rountree, S. D., Chan, W., Pavlik, V. N., Darby, E. J., Siddiqui, S., and Doody, R. S., Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res. Ther., 1, 7 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Roy, S., Zhang, B., Lee, V. M., and Trojanowski, J. Q., Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol., 109, 5–13 (2005).

    Article  PubMed  Google Scholar 

  • Sastre, M., Dewachter, I., Rossner, S., Bogdanovic, N., Rosen, E., Borghgraef, P., Evert, B. O., Dumitrescu-Ozimek, L., Thal, D. R., Landreth, G., Walter, J., Klockgether, T., Van Leuven, F., and Heneka, M. T., Nonsteroidal antiinflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc. Natl. Acad. Sci. U.S.A., 103, 443–448 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Sastre, M., Walter, J., and Gentleman, S. M., Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation, 5, 25 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Sato, T., Hanyu, H., Hirao, K., Kanetaka, H., Sakurai, H., and Iwamoto, T., Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol. Aging, (2009).

  • Schaefer, E. J., Bongard, V., Beiser, A. S., Lamon-Fava, S., Robins, S. J., Au, R., Tucker, K. L., Kyle, D. J., Wilson, P. W., and Wolf, P. A., Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch. Neurol., 63, 1545–1550 (2006).

    Article  PubMed  Google Scholar 

  • Scharf, S., Mander, A., Ugoni, A., Vajda, F., and Christophidis, N., A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology, 53, 197–201 (1999).

    CAS  PubMed  Google Scholar 

  • Schlachetzki, J. C., Fiebich, B. L., Haake, E., De Oliveira, A. C., Candelario-Jalil, E., Heneka, M. T., and Hull, M., Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia. J. Neuroinflammation, 7, 2 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Shen, Y., Li, R., McGeer, E. G., and McGeer, P. L., Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res., 769, 391–395 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Shin, D. W., Kim, S. N., Lee, S. M., Lee, W., Song, M. J., Park, S. M., Lee, T. R., Baik, J. H., Kim, H. K., Hong, J. H., and Noh, M., (−)-Catechin promotes adipocyte differentiation in human bone marrow mesenchymal stem cells through PPAR gamma transactivation. Biochem. Pharmacol., 77, 125–133 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Simard, A. R., Soulet, D., Gowing, G., Julien, J. P., and Rivest, S., Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron, 49, 489–502 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Simic, G., Lucassen, P. J., Krsnik, Z., Kruslin, B., Kostovic, I., Winblad, B., and Bogdanovi, nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer’s disease. Exp. Neurol., 165, 12–26 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Smith, W. L., DeWitt, D. L., and Garavito, R. M., Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem., 69, 145–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Smits, H. A., Rijsmus, A., Van Loon, J. H., Wat, J. W., Verhoef, J., Boven, L. A., and Nottet, H. S., Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J. Neuroimmunol., 127, 160–168 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Soininen, H., West, C., Robbins, J., and Niculescu, L., Longterm efficacy and safety of celecoxib in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord., 23, 8–21 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Stahl, S. M., The new cholinesterase inhibitors for Alzheimer’s disease, Part 2: illustrating their mechanisms of action. J. Clin. Psychiatry, 61, 813–814 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Stewart, W. F., Kawas, C., Corrada, M., and Metter, E. J., Risk of Alzheimer’s disease and duration of NSAID use. Neurology, 48, 626–632 (1997).

    CAS  PubMed  Google Scholar 

  • Streit, W. J., Walter, S. A., and Pennell, N. A., Reactive microgliosis. Prog. Neurobiol., 57, 563–581 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Strohmeyer, R., Shen, Y., and Rogers, J., Detection of complement alternative pathway mRNA and proteins in the Alzheimer’s disease brain. Brain Res. Mol. Brain Res., 81, 7–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Sundararajan, S., Jiang, Q., Heneka, M., and Landreth, G., PPARgamma as a therapeutic target in central nervous system diseases. Neurochem. Int., 49, 136–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Tabner, B. J., El-Agnaf, O. M., Turnbull, S., German, M. J., Paleologou, K. E., Hayashi, Y., Cooper, L. J., Fullwood, N. J., and Allsop, D., Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J. Biol. Chem., 280, 35789–35792 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D., Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., and Tabaton, M., Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol. Dis., 10, 279–288 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Tansey, M. G., McCoy, M. K., and Frank-Cannon, T. C., Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp. Neurol., 208, 1–25 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Taupin, P., Adult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cells. Int. J. Med. Sci., 5, 127–132 (2008).

    CAS  PubMed  Google Scholar 

  • Tchelingerian, J. L., Le Saux, F., and Jacque, C., Identification and topography of neuronal cell populations expressing TNF alpha and IL-1 alpha in response to hippocampal lesion. J. Neurosci. Res., 43, 99–106 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Thal, L. J., Ferris, S. H., Kirby, L., Block, G. A., Lines, C. R., Yuen, E., Assaid, C., Nessly, M. L., Norman, B. A., Baranak, C. C., and Reines, S. A., A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology, 30, 1204–1215 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Tomozawa, Y., Inoue, T., Takahashi, M., Adachi, M., and Satoh, M., Apoptosis of cultured microglia by the deprivation of macrophage colony-stimulating factor. Neurosci. Res., 25, 7–15 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Tong, Y., Zhou, W., Fung, V., Christensen, M. A., Qing, H., Sun, X., and Song, W., Oxidative stress potentiates BACE1 gene expression and Abeta generation. J. Neural. Transm., 112, 455–469 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Trinh, N. H., Hoblyn, J., Mohanty, S., and Yaffe, K., Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA, 289, 210–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Trojanowski, J. Q., Smith, A. B., Huryn, D., and Lee, V. M., Microtubule-stabilising drugs for therapy of Alzheimer’s disease and other neurodegenerative disorders with axonal transport impairments. Expert Opin. Pharmacother., 6, 683–686 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Tuppo, E. E. and Arias, H. R., The role of inflammation in Alzheimer’s disease. Int. J. Biochem. Cell Biol., 37, 289–305 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Turner, P. R., O’Connor, K., Tate, W. P., and Abraham, W. C., Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog. Neurobiol., 70, 1–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Uryu, K., Laurer, H., Mcintosh, T., Pratico, D., Martinez, D., Leight, S., Lee, V. M., and Trojanowski, J. Q., Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J. Neurosci., 22, 446–454 (2002).

    CAS  PubMed  Google Scholar 

  • Vane, J. R., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol., 231, 232–235 (1971).

    CAS  PubMed  Google Scholar 

  • Waldemar, G., Dubois, B., Emre, M., Georges, J., McKeith, I. G., Rossor, M., Scheltens, P., Tariska, P., and Winblad, B., Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur. J. Neurol., 14, e1-26 (2007).

    Google Scholar 

  • Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., and Selkoe, D. J., Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–539 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Wang, D. B., Dayton, R. D., Zweig, R. M., and Klein, R. L., Transcriptome analysis of a tau overexpression model in rats implicates an early pro-inflammatory response. Exp. Neurol., 224, 197–206 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Warner, T. D. and Mitchell, J. A., Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: as easy as ABC? Proc. Natl. Acad. Sci. U.S.A., 100, 9108–9110 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Watson, G. S., Cholerton, B. A., Reger, M. A., Baker, L. D., Plymate, S. R., Asthana, S., Fishel, M. A., Kulstad, J. J., Green, P. S., Cook, D. G., Kahn, S. E., Keeling, M. L., and Craft, S., Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry, 13, 950–958 (2005).

    PubMed  Google Scholar 

  • Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., Kang, D. E., Marquez-Sterling, N., Golde, T. E., and Koo, E. H., A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Wilcock, G. K., Black, S. E., Hendrix, S. B., Zavitz, K. H., Swabb, E. A., and Laughlin, M. A., Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol., 7, 483–493 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., and Husemann, J., Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med., 9, 453–457 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Wyss-Coray, T., Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med., 12, 1005–1015 (2006).

    CAS  PubMed  Google Scholar 

  • Xu, H., Sweeney, D., Greengard, P., and Gandy, S., Metabolism of Alzheimer β-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cellfree system. Proc. Natl. Acad. Sci. U.S.A., 93, 4081–4084 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Yang, F., Lim, G. P., Begum, A. N., Ubeda, O. J., Simmons, M. R., Ambegaokar, S. S., Chen, P. P., Kayed, R., Glabe, C. G., Frautschy, S. A., and Cole, G. M., Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem., 280, 5892–5901 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Yasojima, K., Schwab, C., McGeer, E. G., and McGeer, P. L., Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease. Brain Res., 887, 80–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., and Lee, V. M., Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron, 53, 337–351 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Yu, J. X., Bradt, B. M., and Cooper, N. R., Constitutive expression of proinflammatory complement components by subsets of neurons in the central nervous system. J. Neuroimmunol., 123, 91–101 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Zandi, P. P., Anthony, J. C., Hayden, K. M., Mehta, K., Mayer, L., and Breitner, J. C., Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology, 59, 880–886 (2002).

    CAS  PubMed  Google Scholar 

  • Zhou, Y., Su, Y., Li, B., Liu, F., Ryder, J. W., Wu, X., Gonzalez-Dewhitt, P. A., Gelfanova, V., Hale, J. E., May, P. C., Paul, S. M., and Ni, B., Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science, 302, 1215–1217 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Zhu, X., Su, B., Wang, X., Smith, M. A., and Perry, G., Causes of oxidative stress in Alzheimer disease. Cell. Mol. Life Sci., 64, 2202–2210 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Pharamcy and Medical Research Center, Chungbuk National University, Cheongju, 361-763, Korea

    Young-Jung Lee, Sang Bae Han, Ki-Wan Oh & Jin Tae Hong

  2. Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, 361-763, Korea

    Sang-Yoon Nam

  3. College of Pharmacy, Chungbuk National University, Cheongju, 361-763, Korea

    Jin Tae Hong

Authors
  1. Young-Jung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Bae Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sang-Yoon Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ki-Wan Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin Tae Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Tae Hong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, YJ., Han, S.B., Nam, SY. et al. Inflammation and Alzheimer’s disease. Arch. Pharm. Res. 33, 1539–1556 (2010). https://doi.org/10.1007/s12272-010-1006-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-1006-7

Key words

Search

Navigation