Curcuminoids enhance amyloid-β uptake by macrophages of Alzheimer's disease patients

Zhang, Laura; Fiala, Milan; Cashman, John R.; Sayre, James W.; Espinosa, Araceli; Mahanian, Michelle; Zaghi, Justin; Badmaev, Vladimir; Graves, Michael C.; Bernard, G. W.; Rosenthal, Mark J.

doi:10.3233/jad-2006-10101

Cited by 167 publications

(117 citation statements)

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“…Furthermore, antibody opsonization could increase inflammation (40). Therefore, the enhancement of A␤ phagocytosis (24) and gene transcription in macrophages using the natural substance curcuminoids may have important applications to the immunotherapy of AD. However, it is not clear whether the blood levels achieved after oral administration of curcuminoids would be therapeutic.…”

Section: Discussionmentioning

confidence: 99%

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Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

Fiala

Liu²,

Espinosa‐Jeffrey

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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207

251

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We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-␤ (A␤) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A␤ into endosomes and lysosomes, and AD monocytes do not efficiently clear A␤ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A␤ to endosomes and lysosomes, and monocytes of these subjects clear A␤ in AD brain sections. Upon A␤ stimulation, mononuclear cells of normal subjects up-regulate the transcription of ␤-1,4-mannosyl-glycoprotein 4-␤-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of A␤ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon A␤ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of A␤, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.amyloid-␤ ͉ phagocytosis ͉ endocytosis ͉ MGAT3 siRNA A ccording to the amyloid-␤ (A␤) hypothesis, amyloidosis occurring in the brain of patients with Alzheimer's disease (AD) by fibrillar A␤ 1-42 and 1-40 (1) and A␤ oligomers (2) is a leading cause of neurodegeneration in AD (3). Macrophages and microglia are the innate immune cells responsible for clearance of pathogens and waste products. We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A␤ in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5, 6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A␤ plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9). Thus, the brains of AD patients and transgenic mice seem to display inflammatory responses by microglia and defective A␤ clearance by blood-borne macrophages. Consequently, the defective innate immune system of AD patients might be a culprit in brain amyloidosis leading to brain inflammation.The mechanisms of neurodegeneration produced by abnormally folded proteins, A␤, and phosphorylated remain an enigma (10).The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor...

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Section: Discussionmentioning

confidence: 99%

“…Previously, we reported that a natural product curcuminoids enhanced phagocytosis of A␤ by macrophages from AD patients in Ϸ50% of the cases examined (24). We sought to identify the curcuminoid compound that is most transcriptionally and translationally active.…”

Section: Transcription Of Tlrs In Mononuclear Cells Of Ad Patients Anmentioning

confidence: 99%

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

Fiala

Liu²,

Espinosa‐Jeffrey

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

207

251

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“…In addition to its strong antioxidant ability, it has anti-inflammatory activity, reduces amyloid plaque burden, and partially restored distorted neuritis [125][126][127][128]. A current Phase II clinical trial that combines curcumin and yoga therapy aims to treat MCI (ClinicalTrials.gov identifier: NCT01811381).…”

Section: Oxidative Damage As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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“…amyloid-毬 plaque formation [6][7][8] . Curcumin treatment modulates cellular and humoral immune responses of infected mice and leads to a significant reduction of parasite burden and liver pathology in acute murine schistosomiasis mansoni [9] .…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective and immunomodulatory properties of aqueous extract of Curcuma longa in carbon tetra chloride intoxicated Swiss albino mice

Sengupta

Sharma

Chakraborty

2011

Asian Pacific Journal of Tropical Biomedicine

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Curcuminoids enhance amyloid-β uptake by macrophages of Alzheimer's disease patients

Cited by 167 publications

References 22 publications

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Hepatoprotective and immunomodulatory properties of aqueous extract of Curcuma longa in carbon tetra chloride intoxicated Swiss albino mice

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