Neuroprotection in the CNS

PLoS One. 2012;7(3):e31869. Epub  2012 Mar 19.


A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.


Orlando RA, Gonzales AM, Royer RE, Deck LM, Vander Jagt DL.


Department of Biochemistry and Molecular Biology, University of New Mexico, School of Medicine, Albuquerque, New Mexico, United States of America.


Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcuminis capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized thatcurcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that ofcurcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.



Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12849-54. Epub  2007 Jul 24.


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


Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J.



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-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-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 Abeta 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 Abeta 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 Abeta, 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.



ALZHEIMER AWARD.        2008 Alzheimer Award



Milan Fiala2008 Awardee Milan Fiala, M.D.


Milan Fiala, M.D., a Research Professor of Orthopaedic Surgery at UCLA, Los Angeles, California, received his initial training at the University of Charles IV, Prague, Czechoslovakia and his M.D. degree at the University of Geneva, Switzerland. He obtained a M.Sc.(Epidemiology) from Harvard School of Public Health and pursued translational research in respiratory, herpes and retroviruses viruses at the University of Washington, the University of Pennsylvania and UCLA, where his work played key role in controlling infections of immunocompromised patients.  In the last decade he has developed a modification of the amyloid-beta hypothesis suggesting that the underlying problem of patients with Alzheimer's disease lies in the defectiveness of the innate immune system to clear amyloid-beta in the brain. Dr. Fiala’s laboratory is situated in Orthopaedic Hospital Research Center and includes key UCLA collaborators, John Adams, M.D., Martin Hewison, Ph.D., Philip T. Liu, Ph.D., Araceli Espinosa-Jeffrey, Ph.D., Mark J. Rosenthal, M.D., John M. Ringman, M.D., and research staff including many gifted students. Outside collaborators include John Cashman, Ph.D., HBRI, San Diego; Naoyuki Taniguchi, Osaka University; and Albert S. Lossinsky, New Jersey Neuroscience Institute, Edison, New Jersey.



The work presented in the paper, "Phagocytosis of amyloid-beta and inflammation: two faces of innate immunity in Alzheimer’s disease" (J Alzheimers Dis 11: 1-7, 2007), is a review and a new concept of Alzheimer's disease. The solid data behind the new concept were previously published and showed: a) infiltration of Alzheimer's disease brain by macrophages (Eur J Clin Invest 32:360, 2002); b) irregular clearance of amyloid-beta in plaques (J Alzheimers Dis 7:221-232, 2005); c) enhanced clearance of amyloid-beta by treatment of immune cells with curcuminoids (J Alzheimers Dis 10: 1-7, 2006); and d) defective transcription of genes important for phagocytosis by macrophages of patients (Proc Natl Acad Sci USA 104: 12849-12854, 2007). The basic concept is that physiological balance between phagocytosis and degradation of amyloid-beta and inflammation maintain the pristine condition of neurons. However, in patients with Alzheimer's disease, phagocytosis, degradation of amyloid-beta, and clearance of neurons decrease and inflammation increases due to transcriptional imbalance. In fact, in vitro in brain sections normal macrophages search for neurons (due to a chemokine in neurons), infiltrate and clear neurons of oligomeric and soluble amyloid-beta, whereas macrophages of patients are defective in these functions. However, natural substances, such as curcuminoids, may restore this balance by increasing the transcription of key genes, including Toll-like receptors. Ongoing work based on these concepts will further expand these ideas to develop a blood test for early detection of immune deficiency leading to Alzheimer's disease. It is hoped that these discoveries will lead to all-inclusive approach to Alzheimer's disease:  detection at an early stage and prevention by curcuminoids and other substances, which are likely to be effective before neuronal demise occurs.


Acta Biomater. 2012 Jul;8(7):2670-87. Epub  2012 Apr 4.


Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy.


Kundu P, Mohanty C, Sahoo SK.



Glioblastoma, the most aggressive form of brain and central nervous system tumours, is characterized by high rates proliferation, migration and invasion. The major road block in the delivery of drugs to the brain is the blood-brain barrier, along with the expression of various multi-drug resistance (MDR) proteins that cause the efflux of a wide range of chemotherapeutic drugs. Curcumin, a herbal drug, is known to inhibit cellular proliferation, migration and invasion and induce apoptosis of glioma cells. It also has the potential to modulate MDR in glioma cells. However, the greatest challenge in the administration of curcumin stems from its low bioavailability and high rate of metabolism. To circumvent the above pitfalls of curcumin we have developed curcumin-loaded glyceryl monooleate (GMO) nanoparticles (NP) coated with the surfactant Pluronic F-68 and vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for brain delivery. We demonstrated that our curcumin-loaded NPs inhibit cellular proliferation, migration and invasion along with a higher percentage of cell cycle arrest and telomerase inhibition, thus leading to a greater percentage apoptotic cell death in glioma cells compared with native curcumin. An in vivo study demonstrated enhanced bioavailability of curcumin in blood serum and brain tissue when delivered by curcumin-loaded GMO NPs compared with native curcumin in a rat model. Thus, curcumin-loaded GMO NPs can be used as an effective delivery system to overcome the challenges of drug delivery to the brain, providing a new approach to glioblastoma therapy.