Curcumin Structure-Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease

Abstract

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...

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

“…Alternatively, because amyloid probes can induce HSPs (61), it is possible that curcumin binds to Tau (23) and stimulates HSPs. Nor can we exclude lipid peroxidation and nitration, which are also inhibited by curcumin (25) and influence Tau polymerization and aggregate stability (40,(62)(63)(64). However, in this paradigm, curcumin did not reduce inducible nitricoxide synthase expression (not shown), and these alternatives do not explain the persistence of Ser(P)262 Tau after curcumin treatment.…”

“…All diets were prepared by Harlan Teklad (Madison, WI). Curcumin levels in the brain were determined by LC/MS/MS as previously described (25).…”

“…The diketone bridge of the biphenolic curcumin molecule is essential for anti-amyloidogenic effects in APPsw AD models (25). Because it binds ␤-sheet structures, including NFTs (34) and co-crystallizes with the ␤-sheet core of Tau (23), we sought to determine whether curcumin disrupts Tau aggregation and/or pathogenesis.…”

Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model

“…Recently, it was also demonstrated that the dienone bridge present in CUR is necessary for reducing plaque deposition and protein oxidation in the Alzheimer's model (Begum et al 2008). Frautschy et al (2001) also demonstrated the beneficial effect of CUR treatment in an ICV Aβ peptide injected experimental AD model.…”

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

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