Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer’s disease

Sly, Laurel M.; Krzesicki, Raymond F.; Brashler, John R.; Buhl, Anna-Lena; McKinley, Denise D.; Carter, D.B; Chin, Jeannie

doi:10.1016/s0361-9230(01)00730-4

Cited by 159 publications

(121 citation statements)

References 55 publications

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“…Moreover, enhanced expression of proinflammatory cytokines, such as IL-6, IL-10, IL-1b, TNF-a, are observed in the brain and cerebrospinal fluid (CSF) of Alzheimer's patients (Blum-Degen et al 1995;Jiang et al 2011;Mrak and Griffin 2005;Tarkowski et al 2002). In the animal models of AD, the expression level of TNF-a, IL-1a and IL-1b was also reported to be elevated (Apelt and Schliebs 2001;Benzing et al 1999;Matsuoka et al 2001;Sly et al 2001). The production of these pro-inflammatory cytokines leads to microglial activation, astrogliosis, and induce the release of other pro-inflammatory molecules, amplifying the cytokine effects.…”

Section: Inflammatory Cytokines and Chemokinesmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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Section: Inflammatory Cytokines and Chemokinesmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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“…We have shown that during ME7-induced prion disease, there is an atypical CNS inflammatory response dominated by increases in TGF␤1 with very little contribution from the proinflammatory cytokines interleukin-1␤ (IL-1␤), tumor necrosis factor-␣ (TNF-␣), and interleukin-6 (IL-6) (Betmouni et al, 1996;Walsh et al, 2001;Cunningham et al, 2002). Similarly, low expression of these cytokines has been reported in animal models of AD and Parkinson's disease (Sly et al, 2001;Depino et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

“…We have shown recently that systemic challenge with bacterial endotoxin [lipopolysaccharide (LPS)] provokes exaggerated CNS IL-1␤ synthesis and sickness behavior responses in animals with ongoing chronic inflammation (Combrinck et al, 2002), and this also appears to be true in transgenic models of AD (Sly et al, 2001;Lee et al, 2002). In a previous study, we proposed that microglia in the prion-diseased brain are in a "primed" state, and subsequent challenges, either centrally or systemically, result in an amplified cytokine and inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

Cunningham¹,

Wilcockson²,

Campion³

et al. 2005

J. Neurosci.

673

575

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The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1␤ (IL-1␤) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in priondiseased mice than in control mice and induced microglial expression of IL-1␤. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.

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“…High levels of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF α ) are associated with age-associated neurodegenerative diseases such as Alzheimer's disease (AD) (Fillit et al ., 1991;Malek-Ahmadi, 1998;Rink et al ., 1998;Akiyama et al ., 2000;Albright & Albright, 2000;Lim et al ., 2000;Sly, 2002). This suggests that neuroinflammatory cytokines may be one of the known toxicants including beta-amyloid (Cotman & Su, 1996;Square, 1997;Matsukawa et al ., 2002), presenilins (Cotman & Su, 1996;Furukawa et al ., 1998;Hashimoto et al ., 2002) and free radicals (Smith et al ., 1992(Smith et al ., , 1994Carney & Carney, 1994;Hensley et al ., 1996;Joseph et al ., 1998;McCann et al ., 1998;Butterfield et al ., 1999;Kaufmann et al ., 2001) involved in the neuronal impairments characterizing central nervous system (CNS) aging and the progression of associated diseases.…”

Section: Introductionmentioning

confidence: 99%

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

et al. 2003

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SummaryPerturbations of neuronal physiological homeostasis are likely to underscore neuronal demise/impairments that are reportedly associated with aging of the central nervous system and age-related neurodegenerative diseases such as Alzheimer's disease (AD). A number of ageand/or disease-associated neurotoxic events has been described. These include abnormally modified proteins such as beta amyloid and hyper-phosphorylated Tau, cytokines such as tumour necrosis factor-alpha (TNFα α α α ), high levels of free radicals conducive to oxidative stress, and impaired/decreased neuronal trophic support by neurotrophic factors. Overall, it could be argued that toxic events in the aged brain are either active, such as those due to a direct action of cytokines, or passive, such as those due to lack of growth factor support. It is therefore conceivable that cellular responses to such diverse toxic stimuli are different, suggesting that interventions should be targeted accordingly. In order to begin answering this question, we determined in PC12 cells the time course of activity, in response to TNFα α α α (active) or growth factor withdrawal (passive), of protein kinase c-zeta (PKCζ ζ ζ ζ ), nuclear factor kappa B (NFκ κ κ κ B), caspases 3 and 8, and poly (ADP-ribose) polymerase (PARP), key signal transduction elements associated with modulation of cell death/survival in PC12 cells. We found that the overall activity of PKCζ ζ ζ ζ , NFκ κ κ κ B and caspase 8 was significantly different depending on the apoptotic initiator. The pattern of caspase 3 and PARP activity, however, was not statistically different between serum-free-and TNFα α α α -induced cell death conditions. This suggests that two distinct cell responses are elicited that converge at caspase 3, which then induces downstream events involved in the execution of a common apoptotic programme. These results contribute to the aim of differentially targeting neuronal death in the aged brain (characterized by neurotrophic factor impairments) or in the diseased brain (e.g. AD, characterized by elevated levels of pro-inflammatory cytokines).

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Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer’s disease

Cited by 159 publications

References 55 publications

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

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