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• W2110053544 abstract "Future NeurologyVol. 2, No. 2 EditorialFree AccessEnhancement of innate immunity by curcuminoids and hormones as a therapeutic strategy in neurodegenerative disordersMilan FialaMilan FialaGreater LA VA Medical Center & UCLA School of Medicine, Department of Medicine, 73-084 CHS, UCLA, 650 Charles E Young Drive South, Los Angeles, CA 90095, USA. Search for more papers by this authorEmail the corresponding author at fiala@mednet.ucla.eduPublished Online:20 Feb 2007https://doi.org/10.2217/14796708.2.2.125AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Despite impressive advances in the understanding of the neuropathological basis of Alzheimer’s disease (AD) as being related to neuronal toxicity of amyloid-β (Aβ; 1-40 and 1-42) in fibrillar, soluble or oligomeric form according to the amyloid hypothesis [1], there is as yet no clinically successful strategy to remove Aβ deposits from the brain. In sporadic cases of AD, amyloidosis of the brain may be related to defective clearance of Aβ[2]. Several groups have shown diligent interest in microglial clearance of Aβ [3,4], leading to the development of an Aβ vaccine [5] and a clinical trial, which was, however, abrogated due to adverse encephalitic complications [6]. On the other hand, microglia, with the help of complement and astrocytes, have been shown to be a perpetrator of inflammatory damage in neurodegenerative diseases [7,8], and anti-inflammatory therapies with different nonsteroidal anti-inflammatory drugs have had a continuing vogue [9]. The role of microglia in Aβ clearance was initially proposed as being due to Fc-receptor-mediated phagocytosis and Aβ degradation by microglia [4]. Another strategy for Aβ clearance purports that antibodies can dissolve Aβ deposits [10] and immunoglobulin administration may have beneficial effects in AD patients [11]. In a third scenario, peripherally administered anti-Aβ antibody creates a sink that drains Aβ from the brain [12]. In this editorial we will present our proposals on new strategies for Aβ brain clearance by natural substances to bolster the innate immune system. According to our hypothesis, the normal innate immune system, with the help of adaptive immunity, should be able to clear Aβ from the brain unless there is overproduction of Aβ. We must advise the general readership that the concepts presented below are not yet in the mainstream but are receiving further support from our ongoing studies and those of other investigators.The first issue is the identity of the innate immune cells responsible for Aβ clearance. Traditionally, activated microglia are considered to be responsible for both brain inflammation and Aβ phagocytosis [13,14] through various receptors, including the class B scavenger receptor [15]. Our immunohistochemical studies of AD brain demonstrated that inducible nitric oxide-synthase-positive and cyclooxygenase-2-positive bloodborne monocytes/macrophages penetrate across brain microvessels (with destruction of interendothelial zonula occludes-1 protein) and significantly infiltrate perivascular and parenchymal sites, but only partially clear neuritic plaques [16–18]. These observations suggested that, in addition to microglia, in the human brain with AD, peripheral monocytes/macrophages are the cells involved in Aβ clearance. Our neuropathological results received recent support from studies in animal models of AD. Two groups have demonstrated the ability of peripheral blood macrophages and T cells to invade the brain of aged amyloid-precursor protein transgenic mice [19] and to clear Aβ deposits [20]. We also noted that the density of macrophage infiltration of neuritic plaques was not (inversely) related to residual Aβ (as would be expected if AD macrophages could efficiently clear Aβ) and speculated that the cardinal problem in AD lies specifically in the dysfunction of macrophages. Our studies of over 100 patients and approximately 40 control subjects are revealing unsuspected pathophysiology of AD monocyte/macrophages, which is probably not explained by serum factors since they are noted even in the presence of fetal bovine serum. We are detecting heterogeneous defects in macrophage differentiation in vitro, Aβ uptake and trafficking to lysosomes, and apoptosis on exposure to Aβ. In addition, patients’ monocytes overexpress interleukin-12 and patients’ CD4 T cells overproduce interleukin-10 and interferon-γ, the cytokines belonging to both T helper (Th)1 and Th2 sets. Thus, the adaptive and innate immune system components of AD patients seem to be in various stages of disharmony and dysfunction. In stark contrast, macrophages of control subjects voraciously ingest Aβ and appear to degrade it (probably without the help of antibodies) [17]. In conclusion, we believe that the whole innate immune system (including macrophages and microglia) in AD patients may be defective and its pathological state can be evaluated by studying peripheral blood monocyte/macrophages.The second issue is the classical controversy between the benefits of therapeutic strategies targeting inflammation versus Aβ removal by the immune system. This subject has recently been elegantly reviewed from the point of view of transgenic animal models, with the conclusion that inflammation may induce both beneficial Aβ phagocytic responses and adverse neurotoxic responses [21]. However, the problem is that although current transgenic animals do model brain amyloidosis, albeit iatrogenically, they do not reproduce the immune problem of patients with AD. Therefore, we have been studying the benefits of enhancing immune responses to Aβ using peripheral blood leukocytes of patients and control subjects.Following the demonstration of defective phagocytosis of Aβ by macrophages of a majority of AD patients [17], we have investigated the substances previously shown to be effective in clearance of Aβ plaques in transgenic animals, that is to say curcuminoids [22] and insulin-like growth factor [23]. In cultured macrophages of AD patients in vitro, curcuminoids improved the defect in macrophage phagocytosis of Aβ in 50% of patients in a small study [24]. The responding patients were younger and had higher minimental scores, suggesting that patients in the less advanced stages of AD may respond better. This mechanism of action of curcuminoids is novel and seemingly not in line with the anti-inflammatory and proapoptotic effects of curcuminoids. However, the multitude of regulatory effects of curcuminoids on cell-signaling pathways lends credence to the concept that curcuminoids may be returning the cell to a physiological balance [25]. In addition, we have observed that treatment of AD macrophages with insulin-like growth factor improved Aβ phagocytosis in some macrophages, but we have not yet determined whether hormonal and curcuminoid effects are synergistic or additive. It is tantalizing to speculate whether the effects of immunomodulating and anti-inflammatory therapies could be evaluated in vitro and individualized according to each subject’s innate and adaptive immune responses.In addition to our novel approaches, classical immunological approaches have been proposed to mitigate the encephalitic problem. Microglia have been activated with beneficial and adverse effects using lipopolysaccharide [26] or a proteosome-based adjuvant (Protolin®) [27]. A strong consideration has been given to the possibility that a Th1-cell response against Aβ was responsible for encephalitis in vaccinated subjects and, therefore, strategies to circumvent this complication have been designed using mucosal immunization or using only the B-cell epitope of Aβ for vaccination [28]. In all of these approaches, the adaptive and innate immunity components need to work in unison. Future therapies will need to pay attention to improving both the innate and adaptive immunity.Bibliography1 Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. 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Vaccine22(19),2505–2508 (2004).Crossref, Medline, CAS, Google Scholar11 Istrin G, Bosis E, Solomon B: Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-β peptide. J. Neurosci. Res.84(2),434–443 (2006).Crossref, Medline, CAS, Google Scholar12 DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM: Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA98(15),8850–8855 (2001).Crossref, Medline, CAS, Google Scholar13 McGeer PL, McGeer EG: Inflammation, autotoxicity and Alzheimer’s disease. Neurobiol. Aging22(6),799–809 (2001).Crossref, Medline, CAS, Google Scholar14 Bacskai BJ, Kajdasz ST, Christie RH et al.: Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat. Med.7(3),369–372 (2001).Crossref, Medline, CAS, Google Scholar15 El Khoury JB, Moore KJ, Means TK et al.: CD36 mediates the innate host response to β-amyloid. J. Exp. Med.197(12),1657–1666 (2003).Crossref, Medline, CAS, Google Scholar16 Fiala M, Liu NQ, Reddy S, Graves M: Macrophages infiltrate the brain and express COX-2 and iNOS in Alzheimer’s disease and AIDS. Alzheimer’s Reports4(1),1–7 (2001).Google Scholar17 Fiala M, Lin J, Ringman J et al.: Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer’s disease patients. J. Alzheimers Dis.7(3),221–232 (2005).Crossref, Medline, CAS, Google Scholar18 Fiala M, Liu QN, Sayre J et al.: Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood-brain barrier. Eur. J. Clin. Invest.32(5),360–371 (2002).Crossref, Medline, CAS, Google Scholar19 Stalder AK, Ermini F, Bondolfi L et al.: Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci.25(48),11125–11132 (2005).Crossref, Medline, CAS, Google Scholar20 Simard AR, Soulet D, Gowing G, Julien JP, Rivest S: Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron49(4),489–502 (2006).Crossref, Medline, CAS, Google Scholar21 Wyss-Coray T: Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med.12(9),1005–1015 (2006).Medline, CAS, Google Scholar22 Yang F, Lim GP, Begum AN et al.: Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem.280(7),5892–5901 (2005).Crossref, Medline, CAS, Google Scholar23 Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I: Serum insulin-like growth factor I regulates brain amyloid-β levels. Nat. Med.8(12),1390–1397 (2002).Crossref, Medline, CAS, Google Scholar24 Zhang L, Fiala M, Cashman J et al.: Curcuminoids enhance amyloid-β uptake by macrophages of Alzheimer’s disease patients. J. Alzheimers Dis.10,1–7 (2006).Crossref, Medline, Google Scholar25 Shishodia S, Sethi G, Aggarwal BB: Curcumin: getting back to the roots. Ann. NY Acad. Sci.1056,206–217 (2005).Crossref, Medline, CAS, Google Scholar26 Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein F: Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer’s disease. J. Neuroimmunol.137(1–2),32–41 (2003).Crossref, Medline, CAS, Google Scholar27 Frenkel D, Maron R, Burt DS, Weiner HL: Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease. J. Clin. Invest.115(9),2423–2433 (2005).Crossref, Medline, CAS, Google Scholar28 Weiner HL, Frenkel D: Immunology and immunotherapy of Alzheimer’s disease. Nat. Rev. Immunol.6(5),404–416 (2006).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 2, No. 2 Follow us on social media for the latest updates Metrics Downloaded 418 times History Published online 20 February 2007 Published in print March 2007 Information© Future Medicine LtdPDF download" @default.
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