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...

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.

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.