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...

Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1β. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble β-amyloid peptide (Aβ), and carbonyls. TC had no impact on plaques or insoluble Aβ, but both reduced Tris-buffered salinesoluble Aβ and phospho-c-Jun NH 2 -terminal kinase (JNK). Curcumin but not TC prevented Aβ aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Aβ, effects that may be attributable to limiting JNKmediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.Neuroinflammation is implicated in the pathogenesis of many neurodegenerative disorders, including Alzheimer's disease (AD). In AD, several mediators in the inflammation cascade contribute both to neurodegeneration and to the production and accumulation of the β-amyloid peptide, including interleukin (IL)-1β, phospho-c-Jun NH 2 -terminal kinase (pJNK), reactive oxygen species, inducible nitric-oxide synthase (iNOS)-mediated production of reactive nitric oxide species, and lipid peroxidation products (e.g., 8-iso-PGF 2 α) (for review, see Akiyama Address correspondence to: Dr. Sally A. Frautschy, Departments of Medicine/Neurology UCLA, Greater Los Angeles Healthcare System, VA Medical Center, Research 151, 16111 Plummer St., Sepulveda, CA 91343. E-mail: frautsch@ucla.edu. et al., 2000). For AD therapeutics, there is rationale to develop drugs that attenuate inflammatory cascades contributing to neurodegeneration and amyloid production or accumulation. However, there is concern that some anti-inflammatory drugs may interfere with phagocytic clearance of amyloid. Curcumin, a compound known to inhibit inflammation while reducing plaque deposition in AD models, is the yellow pigm...

IntroductionCurcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.MethodsWe performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.ResultsMean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).ConclusionsCurcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.Trial registrationClinicalTrials.gov Identifier: NCT00099710.

Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)