Alzheimer's disease (AD) involves amyloid ␤ (A␤) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and antiinflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential A␤ binding, we investigated whether its efficacy in AD models could be explained by effects on A␤ aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC 50 ‫؍‬ 0.8 M) as well as disaggregated fibrillar A␤40 (IC 50 ‫؍‬ 1 M), indicating favorable stoichiometry for inhibition. Curcumin was a better A␤40 aggregation inhibitor than ibuprofen and naproxen, and prevented A␤42 oligomer formation and toxicity between 0.1 and 1.0 M. Under EM, curcumin decreased dose dependently A␤ fibril formation beginning with 0.125 M. The effects of curcumin did not depend on A␤ sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small ␤-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates A␤ as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.The 4-kDa (40 -42-amino acid) amyloid-␤ peptide (A␤) 1 is derived from the amyloid precursor protein (APP) through sequential proteolysis by the aspartyl protease ␤-secretase and presenilin-dependent ␥-secretase cleavage (1). Mutations at the cleavage sites in APP or in presenilin that increase production or aggregation of A␤ provide a compelling argument for a central role for A␤ aggregation in the pathogenesis of Alzheimer's disease (AD). The progressive accumulation of A␤ aggregates is widely believed to be fundamental to the initial development of neurodegenerative pathology and to trigger a cascade of events such as neurotoxicity, oxidative damage, and inflammation that contribute to the progression of AD (2-5). Therefore, many therapeutic efforts are targeted at reducing A␤ production, including inhibiting secretase, increasing A␤ clearance with amyloid vaccines, or blocking A␤ aggregation (with antibodies, peptides, or small organic molecules that selectively bind and inhibit A␤ aggregate and fibril formation).A␤ fibrillization involves formation of dimers and small oligomers followed by growth into protofibrils and fibrils via a complex multistep-nucleated polymerization. Polymerizing A␤ fibrils and intermediates can be stained by amyloidophilic dyes such as Cong...

Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

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-1beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Abeta. 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.