Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease

Lim, Giselle P.; Yang, Fusheng; Chu, Teresa; Chen, P.; Beech, Walter; Teter, Bruce; Tran, Thuy; Ubeda, Oliver J.; Ashe, Karen H.; Frautschy, Sally A.; Cole, Greg M.

doi:10.1523/jneurosci.20-15-05709.2000

Cited by 829 publications

(620 citation statements)

References 34 publications

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“…ajp.amjpathol.org -The American Journal of Pathology Total Ab levels were measured with the use of a sandwich ELISA as described previously. 39 Concentrations of Ab oligomers and total Ab in each sample were normalized against the total protein concentration measured with the use of Pierce BCA Protein Assay Kit according to the manufacturer's protocol.…”

Section: Oligomeric and Total Ab Elisamentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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Section: Oligomeric and Total Ab Elisamentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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“…A␤ immunohistochemistry was done with DAE (rabbit anti-human A␤ antibody; [13]; kindly provided by Greg Cole, UCLA) using the Vectastain Rabbit Elite ABC kit (Vector/Novocastra) and development with TrueBlue Substrate (KPL). Staining of brain architecture and neurons was carried out with 0.2% cresyl violet acetate solution.…”

Section: Histologymentioning

confidence: 99%

“…Neuronal damage/death can also induce glial activation, facilitating the propagation of a localized, detrimental cycle of neuroinflammation [8]. Accumulating evidence [1,6,9,13] suggests that targeting this glia-neuron cycle might be a therapeutic approach to Alzheimer's disease (AD) progression. However, progress in the pursuit of neuroinflammation as a therapeu-tic target in AD requires proof of concept that selective suppressors of glial activation can selectively modulate neuropathogenic aspects of the neuroinflammatory cycle, without impeding beneficial glial responses, in a robust animal model of AD-relevant neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (A␤)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human A␤1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1␤, tumor necrosis factor-␣ and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress A␤-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

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“…These epidemiological findings have been supported by experimental studies. First, chronic ibuprofen (Ibu) treatment significantly diminished amyloid deposition (Lim et al, 2000), and improved behavioral impairment in the APPsw transgenic mouse (Tg2576) (Lim et al, 2001). Second, a subset of NSAIDs such as Ibu, sulindac sulfide (SSide), indomethacin (Ind) (Weggen et al, 2001) and flurbiprofen (Flu) selectively decreased the secretion of Aß(1-42) from cultured cells independently of cyclooxygenase (COX) activity and lowered the amount of soluble in the brains of Tg2576 mouse.…”

Section: Introductionmentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

et al. 2005

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The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid ß-peptides (Aß) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term uses of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD and delay the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of ß-amyloid fibrils (fAß) at pH 7.5 at 37˚C in vitro. All examined NSAIDs dose-dependently inhibited formation of fAß from fresh Aß(1-40) and Aß(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fAßs. The overall activity of the molecules examined was in the following order: ibuprofen ≈ sulindac sulfide ≥ meclofenamic acid sodium salt > aspirin ≈ ketoprofen ≥ flurbiprofen ≈ diclofenac sodium salt > naproxen ≈ indomethacin. Although the mechanisms by which these NSAIDs inhibit fAß formation from Aß, and destabilize preformed fAß in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

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Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease

Cited by 829 publications

References 34 publications

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro

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