Massive gliosis induced by interleukin‐6 suppresses Aβ deposition
            <i>in vivo:</i>
            evidence against inflammation as a driving force for amyloid deposition

Chakrabarty, Paramita; Jansen-West, Karen; Beccard, Amanda; Ceballos‐Diaz, Carolina; Levites, Yona; Verbeeck, Christophe; Zubair, Abba C.; Dickson, Dennis W.; Golde, Todd E.; Das, Pritam

doi:10.1096/fj.09-141754

Cited by 281 publications

(250 citation statements)

References 48 publications

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“…There is a large amount of evidence to show that increased proinflammatory cytokines correlates with Aβ production and neurodegeneration. In contrast, there are also a number of studies indicating that proinflammatory cytokines precondition the system for Aβ challenge and protect against neurodegeneration (82)(83)(84)(85). Clearly, inflammation is a major component of the AD brain, and more work will be required in order to elucidate its role in AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Ly¹,

Wu²,

Zou³

et al. 2012

J. Clin. Invest.

350

223

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Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β-and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Ly¹,

Wu²,

Zou³

et al. 2012

J. Clin. Invest.

350

223

View full text Add to dashboard Cite

show abstract

“…For instance, induction of the proinflammatory cytokines IL-1β, TNF-α, IL-6, and IFN-γ correlated with reduced Aβ deposition in AD mouse models (23)(24)(25)(26). Recently, TNF-α receptor ablation was shown to enhance AD pathology in transgenic mice, likely because of impaired Aβ phagocytosis (27).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

Michaud

Hallé

Lampron

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

229

162

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Alzheimer's disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APP swe /PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.lzheimer's disease (AD) is a neurodegenerative pathology characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in the brain parenchyma (1). Inflammation, which occurs in parallel with the progression of the disease, is featured by the production of cytokines by activated microglia. The role of these cells in the pathogenesis of AD remains unclear and is an area of active investigation. Whereas chronic activation of microglial cells by Aβ can trigger the exaggerated release of cytokines and neurotoxic mediators that could be detrimental to neurons, microglia can also clear Aβ via increased phagocytosis and proteolytic degradation, which may be neuroprotective (2).Toll-like receptors (TLRs) on the surface of microglial cells have been shown to bind Aβ, which triggers downstream intracellular signaling cascades (3, 4). Microglia deficient in TLR2, TLR4, or the coreceptor CD14 are not activated by Aβ and do not exhibit a phagocytic response (5). Transgenic AD mice lacking TLR4 have markedly elevated levels of diffuse and fibrillar Aβ (3). Furthermore, stimulation of microglial cells with TLR2-, TLR4-, or TLR9-specific agonists accelerates Aβ clearance both in vitro and in vivo (3, 6, 7).Monophosphoryl lipid A (MPL) is a chemically detoxified lipid A moiety derived from Salmonella minnesota R595 LPS (8). This TLR4 ligand is at least 100-fold less pyrogenic than LPS yet maintains many of the immunomodulatory properties of LPS (9). Importantly, MPL is safe in humans and has been administered to millions of patients as a component of several vaccine formulations such as the Cervarix vaccine (10). We investigated herein the chronic use of the nonpyrogenic TLR4 agonist MPL and compared it with a strong TLR4 ligand (LPS) in a mouse model of AD.Although the therapeutic potential of innate immune activation for AD is being evaluated in preclinical models, this conc...

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“…Similarly, early overexpression of IL-6, another pleiotropic pro-inflammatory cytokine elevated in patients with AD, in APP transgenic TgCRND8 and Tg2576 mice induces enhanced gliosis and decreased A␤ pathological features. 93 Furthermore, the same group demonstrated increased microglial phagocytosis and elevated phagocytic marker expression, concluding that IL-6 promotes A␤ clearance mediated by microglial phagocytosis. Our results indicate that abrogation of TNF-␣ receptor signaling over a protracted period intensifies extracellular A␤ deposition, whereby 3xTg-ADxTNF-RI/RII KO mice have elevated soluble A␤ 42 , insoluble A␤ 40 , and insoluble A␤ 42 protein levels (Figure 6, E-G).…”

mentioning

confidence: 89%

Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology

Montgomery

Mastrangelo

Habib

et al. 2011

The American Journal of Pathology

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-␣, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-␣ is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-␣ signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-␣ receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-␣ receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-␣. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-␤ phagocytic marker expression and phagocytosis activity, indicating that intact TNF-␣ receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-␤ peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-␣ inhibitors for the treatment of

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Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition

Cited by 281 publications

References 48 publications

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology

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