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

By Giselle P. Lim, Fusheng Yang, T. Chu, Patrick B. Chen, W. Beech, B. Teter, Tracy S. Tran, O. Ubeda, K. Ashe, S. Frautschy and 1 more. Journal of Neuroscience, 2000

946 citations recorded by the source corpus.

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg−) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1β and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of β-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Aβ. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Subfields: Biological Psychiatry, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/58ac7f6b731be1e8f2638a653a20595211787911

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Citations in the corpus

Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease (2008, neutral): “body; Sigma-Aldrich) as described previously (Lim et al., 2000).”
Molecular Inflammation: Underpinnings of Aging and Age-related Diseases (2008, background): “A high dose of ibuprofen markedly suppressed amyloid plaque pathology and Aβ levels, reduced microglial activation and reactive astrocyte numbers, and decreased levels of the proinflammatory cytokine IL-1β (Lim et al., 2000).”
Inflammation in Alzheimer disease: driving force, bystander or beneficial response? (2006, background): “In the first such study, ibuprofen had a beneficial effect in APP transgenic mic”
The role of microglia in amyloid clearance from the AD brain (2010, background): “Treating AD mice with anti-inflammatory agents, such as LXR agonist, PPARc agonists and non-steroidal anti-inflammatory drugs (NSAIDs), resulted in enhanced phagocytosis in response to fAb and ameliorated AD pathology (Heneka et al. 2005; Lim et al. 2000; Zelcer et al. 2007).”
Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. (2003, background): “In transgenic mice with AD-type amyloid deposition, the NSAID ibuprofen reduced brain inflammation and levels of soluble and insoluble amyloid peptide, and improved behavior.(8,9) In this trial, we tested the hypothesis that NSAID treatment would slow the rate of cognitive decline in participants wi”
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity (2001, background): “Ibuprofen reduced amyloid plaque pathology in a mouse model of Alzheimer's disease, and indomethacin seemed to slow the cognitive decline in patients with Alzheimer's disease in a placebo-controlled pilot stud”
Long-term potentiation and memory. (2004, background): “Evidence of oxidative stress has also been identified in transgenic mouse models of AD (575), and this is accompanied by an increase in IL-1 concentration and -amyloid deposition, both of which are attenuated by ibuprofen treatment (326).”
Aggravation of Alzheimer’s disease due to the COX-2-mediated reciprocal regulation of IL-1β and Aβ between glial and neuron cells (2014, background): “However, recent studies revealed that long-term in vivo treatment of amyloid precursor protein (APP) transgenic mice with NSAIDs significantly diminished Ab deposition (Lim et al., 2000) and improved behavior (Lim et al., 2001).”
Neuropathologic changes in Alzheimer's disease. (2003, background): “9 J Clin Psychiatry 2003;64 (suppl 9) cologically related compounds with analgesic, antipyretic, and anti-inflammatory properties, can modify the generation of the amyloid peptide in brain.(16) Transgenic mice developed amyloid plaques with inflammatory activity that models Alzheimer’s disease amylo”
The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse (2001, methodology): “We thank Dr. Karen Hsiao Ashe for her continued support and collaboration in studies pertaining to the Tg2576 mouse.”
Inflammatory Neurodegeneration Mediated by Nitric Oxide from Activated Glia-Inhibiting Neuronal Respiration, Causing Glutamate Release and Excitotoxicity (2001, background): “, 1998), and anti-inflammatory drugs protect against Alzheimer’s disease (McGeer and McGeer, 1995; McGeer et al., 1996; Lim et al., 2000).”
Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders (2010, neutral): “compared to United States (102, 259, 469).”