Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Role of Retinoids in Treatment of Alzheimer's Disease


Affiliations
1 KCT's Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri, Nashik-13, India
     

   Subscribe/Renew Journal


Alzheimers disease very basically is characterized by the loss of the cognitive functions. β-amyloid is a major histopathological hallmark of Alzheimer's disease (AD). The disease is characterized by extracellular neuritic plaque composed of fibrillar-amyloid peptide and intracellular neurofibrillary tangles containing hyperphosphorylated tau. The peptides are generated by successive proteolysis of beta amyloid precursor protein, a large transmembrane glycoprotein that is initially cleaved by the site amyloid precursor protein cleaving enzyme -1 and subsequently by gamma secretase in the transmembrane domain. Retinoic acid is active metabolite of Vitamin A. Deprivation of Vitamin A results in amyloid-β accumulation, loss of hippocampal long term potentiation and memory deficit, all of which are hall mark of Alzheimers disease. Here we focused a role of retinoic acid on different pathophysiological features of Alzheimers disease. Retinoic acid may play an active role in treating neurodegenerative disorder. Retinoids appear to normalize many pathological states, and clinical side effects presently reported are mostly not serious except for retinoic acid syndrome.

Keywords

Alzheimers, Retinoic Acid, Vitamin A, Amyloid-β, Retinoid X Receptor(RXR).
Subscription Login to verify subscription
User
Notifications
Font Size


  • Culvenor JG, Evin G, Cooney MA, Wardan H, Sharples RA, Maher F, et al. Presenlin expression 2 neuronal cell : Induction during differentiation of embryonic carcinoma cells. Experimental Cell Research. 255 ; 2000:192.
  • Lahiri S, Buerk DG, Chugh D, Osanai S, Mokashi, A. Reciprocal phoolabile O2 consumption and chemoreceptor excitation by carbon monoxide in the cat carotid body: evidence for cytochrome a3 as the primary O2 sensor. Brain Research. 684; 1995:194.
  • Hong CS, Caromile L, Nomata Y, Mori H, Bredesen DE, Koo EH. Contrasting role of presenilin-1 and presenilin-2 in neuronal differentiation in vitro. Journal of Neuroscience. 19; 1999:637.
  • Satoh J, Kuroda Y. Amyloid precursor protein beta-secretase (BACE) mRNA expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines and growth factors. Neuropathology.20; 2000:289.
  • Yang Y, Quitschke WW, Brewer GJ. Up regulation of amyloid precursor protein gene promoter in rat primary hippocampal neurons by phorbol ester, IL-1 and retinoic acid, but not by reactive oxygen species. Brain Res Mol Brain Res.60; 1998:40.
  • Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 83;1995: 841.
  • Holland, Linda Z, "Developmental biology: A chordate with a difference". Nature. 447; 2007:153.
  • Cocco S, Diaz G, Stancampiano R, Diana A, Carta M, Curreli R, Sarais L, et al. Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience.115;2002:475.
  • Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signaling. Behavioral Brain Research.145;2003:37.
  • Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. Journals of Alzheimers Disease. 3;2001:75.
  • Wenk GL. Neuropathologic Changes in Alzheimer's disease. Journal of Clinical Psychiatry. 64; 2003:7.
  • Lipton SA. Paradigm shift in neuroprotection by ofNMDA receptor blockade: memantine and beyond. Nature Review Drug Discovery. 5;2006:160.
  • Palmer AM, Wilock GK, Esiri MM, Francis PT and Bowen DM. Monoaminergic innervation of the frontal and temporal lobes in alzheimer's disease. Brain Research. 40;11987: 2238.
  • Leake A, Moore PB, Leitch M, Ayre K, Perry RH, Ince PG, et al.The serotonergic system in Alzheimer's disease and normal neocortical post mortem brain: neurochemical and clinical correlates. Neurology Psychiatry and Brain Research. 2;1993:53.
  • Yates CM, Simpson J, Gordon A, Maloney AFJ, Allison Y, Ritchie IM, et al. Catecholamine and cholinergic enzymes in pre senile and senile Alzheimer type dementia and Down's syndrome. Brain Research. 280;1983:119.
  • Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P. Greengard P et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. Journal of American Medical Association. 283; 2000:1571.
  • Chen GQ, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, et al. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 408;2000:975.
  • The National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's disease. In Consensus recommendations for the post-mortem diagnosis of Alzheimer's disease. Neurobiology Aging.; 18;1997: S1-S2.
  • Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001; 293:1487.
  • Citron M. Alzheimer's disease: Treatments in discovery and development. Nature Neuroscience. 5;2002:1055.
  • DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM and 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. Procedings of National Academy of Sciences USA. 98 ;2001:8850.
  • Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood.111;2008:2505.
  • Miwako I, Kagechika H, Tamibarotene. Drugs Today (Barc). 43;2007:563.
  • Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H. RAR and RXR modulation in cancer and metabolic disease. Nature Review Drug Discovery. 6;2007:793.
  • Oikawa T, Okayasu I, Ashino H, Morita I, Murota S, Shudo K.Three novel synthetic retinoids, Re 80, Am 580 and Am 80, all exhibit anti-angiogenic activity in vivo. European Journal of Pharmacology. 249;1993:113-116.
  • Sardana K, Sehgal VN. Retinoids: fascinating up-and-coming scenario. Journal of Dermatology. 30;2003:355.
  • Ishibashi Y. Clinical Effect of Am-80 Ointment on Psoriasis and Pustulosis Palmaris et Plantaris (Phase Study). RinshouIyaku.11;1995:747.
  • Nickoloff BJ. Cracking the cytokine code in psoriasis. Nature Medicine.13;2007:242.
  • Kuwabara K, Shudo K, Hori Y. Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels. FEBS Letter.378;1996:53.
  • Nagai H, Matsuura S, Bouda K, Takaoka Y, Wang T, Niwa S. Effect of Am-80, a synthetic derivative of retinoid, on experimental arthritis in mice. Pharmacology. 58;1999:101.
  • Beehler BC, Brinckerhoff CE, Ostrowski J. Selective retinoic acid receptor ligands for rheumatoid arthritis.Current Opinion Investigation Drugs.5;2004:1153.
  • Wiegman PJ, Barry WL, McPherson JA, McNamara CA, Gimple LW, Sanders JM. All-trans-retinoic acid limits restenosis after balloon angioplasty in the focally atherosclerotic rabbit: A favorable effect on vessel remodeling. Arteriosclerosis, Thrombosis and Vascular Biology. 20;2000:89.
  • Fujiu K, Manabe I, Ishihara A, Oishi Y, Iwata H, Nishimura G. Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5.Circulation Research. 97;2005:1132.
  • Sato M, Shudo K, Hiragun A. Functional studies of newly synthesized benzoic acid derivatives: identification of highly potent retinoid-like activity. Journal of Cell Physiology. 135;1988:179.
  • Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nature Medicine. 3;1997:675.
  • Nishikiori N, Osanai M, Chiba H, Kojima T, Mitamura Y, Ohguro H. Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy. Diabetes. 56;2007:1333.
  • Nishikiori N, Osanai M, Chiba H, Kojima T, Ohguro H, Sawada N. Inhibitory effects of retinoic acid receptor alpha stimulants on murine cataractogenesis through suppression of deregulated calpains. Investigative Ophthalmology and Visual Science.48;2007:2224.
  • Miwako I, Shudo K. Oral administration of synthetic retinoid Am80 inhibits the development of type 1 diabetes in NOD mice. Biological and Pharmceutical Bulletin. 32(1);2009:157-159
  • Osanai M, Nishikiori N, Murata M, Chiba H, Kojima T, Sawada N. Cellular retinoic acid bioavailability determines epithelial integrity: Role of retinoic acid receptor alpha agonists in colitis. Molecular Pharmacology.71;2007:250.
  • Phase Study of RR110 in Patients with Active Crohn's Disease [online]. Available from URL: http://clinicaltrials.gov/ct2/show/ NCT00417391 [Accessed 2008 July 7]
  • Standeven AM, Teng M, Chandraratna RA. Lack of involvement of retinoic acid receptor alpha in retinoid-induced skin irritation in hairless mice. Toxicology Letter.92;1997:231.
  • Iulianella A, Lohnes D. Contribution of retinoic acid receptor gamma to retinoid-induced craniofacial and axial defects. Developmental Dynamics.209;1997: 92-104.
  • Look J, Landwehr J, Bauer F, Hoffmann AS, Bluethmann H, LeMotte P. Marked resistance of RAR gamma-deficient mice to the toxic effects of retinoic acid. American Journal of Physiology. 269;1995: E91-98.
  • Reczek PR, Ostrowski J, Yu KL, Chen S, Hammer L, Roalsvig T, et al. Role of retinoic acid receptor gamma in the Rhino mouse and rabbit irritation models of retinoid activity. Skin Pharmacology. 8;1995: 292-299.
  • Misner DL, Jacobs S, Shimizu Y, de Urquiza AM, Solomin L, Perlmann T, et al. Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Procedings of National Academy of Sciences USA. 98;2001: 11714- 11719.
  • Mingaud F, Mormede C, Etchamendy N, Mons N, Niedergang B, Wietrzych M, et al. Retinoid hyposignaling contributes to aging-related decline in hippocampal function in shortterm/ working memory organization and long-term declarative memory encoding in mice. Journal of Neuroscience.28;2008: 279-291.
  • Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Procedings of National Academy of Sciences USA..100;2003: 2901-2905.
  • Goodman AB. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. Journal of Cellular Physiology. 209;2006:598-603.
  • Farooqui AA, Antony P, Ong Wei-Yi, Horrocks LA, Freysz L. Retinoic acid-mediated phospholipase A2 signaling in the nucleus. Brain research reviews. 45;2004: 179-195.
  • Kobayashi M, Matsuoka I, Kurihara K. Cholinergic differentiation of cultured sympathetic neurons induced by retinoic acid. Induction of choline acetyltransferase-mRNA and suppression of tyrosine hydroxylase-mRNA levels. FEBS Letter.337;1994: 259-264.
  • Pedersen WA, Berse B, Schuler U, Wainer BH, Blusztajn JK. All-trans- and 9-cis-retinoic acid enhance the cholinergic properties of a murine septal cell line: evidence that the effects are mediated by activation of retinoic acid receptor-alpha. Journal of Neurochemistry. 65;1995: 50-58.
  • Berse B, Blusztajn JK. Coordinated up-regulation of choline acetyl-transferase and vesicular acetylcholine transporter gene expression by the retinoic acid receptor alpha, cAMP, and leukemia inhibitory factor/ciliary neurotrophic factor signaling pathways in a murine septal cell line. Journal of Biological Chemistry. 270;1995: 22101-22104.
  • Samad TA, Krezel W, Chambon P, Borrelli E. Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptorretinoid X receptor family. Procedings of National Academy of Sciences USA. 94;1997:14349-14354.
  • Husson M, Enderlin V, Delacourte A, Ghenimi N, Alfos S, Pallet V, et al. Retinoic acid normalizes nuclear receptor mediated hypoexpression of proteins involved in beta-amyloid deposits in the cerebral cortex of vitamin A deprived rats. Neurobiology of Disease. 23;2006:1-10.
  • Corcoran J P, So P L, Maden M. Disruption of the retinoid signalling pathway causes a deposition of amyloid beta in the adult rat brain. European Journal of Neuroscience.20;2004: 896-902.
  • Prinzen C, Muller U, Endres K, Fahrenholz F, Postina R. Genomic structure and functional characterization of the human ADAM10 promoter. FASEB J. 19;2005:1522-1524.
  • Fahrenholz F, Postina R. Alpha-secretase activation--an approach to Alzheimer's disease therapy. Neurodegenerative Disease. 3; 2006:255-261.
  • Fahrenholz F. Alpha-secretase as a therapeutic target. Current Alzheimer Research.4;2007: 412-417.
  • Britschgi M, Wyss-Coray T. Immune cells may fend off Alzheimer disease. Nature Medicine.13;2007: 408-409.
  • El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine.13;2007:432-438.
  • Tehranian R, Hasanvan H, Iverfeldt K, Post C, Schultzberg M. Early induction of interleukin-6 mRNA in the hippocampus and cortex of APPsw transgenic mice Tg2576. Neuroscience Letter.301;2001:54-58.
  • Bhojak TJ, DeKosky ST, Ganguli M, Kamboh MI. Genetic polymorphisms in the cathespin D and interleukin-6 genes and the risk of Alzheimer's disease. Neuroscience Letter.288;2000: 21-24.
  • Shibata N, Ohnuma T, Takahashi T, Baba H, Ishizuka T, Ohtsuka M, et al. Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. American Journal of Medical Genetics.114; 2002: 436-439.
  • Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T elper cells. Cell.126;2006:1121-1133.
  • Schwab C, McGeer PL. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. Journal of Alzheimers Disease.13;2008: 359-369.
  • Miklossy J. Chronic inflammation and amyloidogenesis in Alzheimer's disease -- role of spirochetes. Journal of Alzheimers Disease.13;2008: 381-391.
  • Itzhaki RF, Wozniak MA. Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. Journal of Alzheimers Disease. 13; 2008: 393-405.
  • Balin BJ, Little CS, Hammond CJ, Appelt DM, Whittum- Hudson JA, Gerard HC, et al. Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. Journal of Alzheimers Disease.13; 2008: 371-380.
  • Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Review Immunology. 7; 2007: 161-167.
  • Doty RL. The olfactory vector hypothesis of neurodegenerative disease: is it viable? Annals Neurology. 63; 2008: 7-15.
  • Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K, et al. Association of olfactory dysfunction with risk for future Parkinson's disease. Annals Neurology.63; 2008: 167-173.
  • Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, et al. A 10-item smell identification scale related to risk for Alzheimer's disease. Annals Neurology. 58; 2005:155-160.
  • Rawson NE, LaMantia AS. Once and again: retinoic acid signaling in the developing and regenerating olfactory pathway. Journal of Neurobiology. 66;2006: 653-676.
  • Rawson NE, LaMantia AS. A speculative essay on retinoic acid regulation of neural stem cells in the developing and aging olfactory system. Experimental Gerontology. 42;2007:46-53.
  • Mey J, Morassutti DJ. Brook G, Liu RH, Zhang YP, Koopmans G, et al. Retinoic acid synthesis by a population of NG2- positive cells in the injured spinal cord. European Journal of Neuroscience. 21; 2005: 1555-1568.
  • Mey J. New therapeutic target for CNS injury? The role of retinoic acid signaling after nerve lesions. Journal of Neurobiology. 66; 2006: 757-779.
  • Kern J, Schrage K, Koopmans GC, Joosten EA, McCaffery P, Mey J. Characterization of retinaldehyde dehydrogenase-2 induction in NG2-positive glia after spinal cord contusion injury. International Journal of Developmental Neuroscience. 25;2007: 7-16.
  • Zhelyaznik N, Mey J. Regulation of retinoic acid receptors alpha, beta and retinoid X receptor alpha after sciatic nerve injury. Neuro-science.141;2006: 1761-1774.
  • Mey J, Schrage K, Wessels I, Vollpracht-Crijns I. Effects of inflammatory cytokines IL-1beta, IL-6, and TNF alpha on the intracellular localization of retinoid receptors in Schwann cells. Glia.; 55;2007: 152-164.
  • Maden M, Hind M. Retinoic acid, a regeneration-inducing molecule.Developmental Dynamics.226;2003: 237-244.
  • Vergara MN, Arsenijevic Y, Del Rio-Tsonis K. CNS regeneration: a morphogen's tale. Journal of Neurobiology.64; 2005: 491-507.
  • Strickland S, Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell.15; 1978: 393- 403.
  • Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Progress in Neurobiology.75; 2005:275-280.
  • Chiang MY, Misner D, Kempermann G, Schikorski T, Giguere V, Sucov HM. An essential role for retinoid receptors RARbeta and RXR gamma in long-term potentiation and depression. Neuron. 21;1998:1353.
  • Etchamendy N, Enderlin V, Marighetto A, Vouimba RM, Pallet V, Jaffard R. Alleviation of a selective age-related relational memory deficit in mice by pharmacologically induced normalization of brain retinoid signaling. Journal of Neuroscience. 21;2001:6423-6428.
  • Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behavioural Brain Research.145;2003:37.
  • Huang JTJ, Leweke FM, Oxley D, Wang L, Harris N et,al. Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis PLoS Med. 2006; 3: e428 Available from: www.ncbi.nlm.nih.gov/pubmed/17090210
  • Brouillette J, Quirion R. Transthyretin: A key gene involved in the maintenance of memory capacities during aging. Neurobiology Aging. 29;2008:1721.
  • Monaco HL. The transthyretin-retinol-binding protein complex. Biochimica et Biophysica Acta. 1482;2000:65.
  • Merched A, Serot JM, Visvikis S, Aguillon D, Faure G, Siest G. Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry. FEBS Letter.425;1998:225.
  • Schwarzman AL, Gregori L, Vitek MP, Lyubski S, Strittmatter WJ, Enghilde JJ, Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proceedings of National Academy of Sciences USA. 91;1994:8368.
  • Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum a insulin-like growth factor I regulates brain amyloidbeta levels. Nature Medicine. 8;2002:1390.

Abstract Views: 234

PDF Views: 2




  • Role of Retinoids in Treatment of Alzheimer's Disease

Abstract Views: 234  |  PDF Views: 2

Authors

R. B. Saudagar
KCT's Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri, Nashik-13, India
V. V. Buchake
KCT's Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri, Nashik-13, India
R. S. Bachhav
KCT's Ravindra Gambhirrao Sapkal College of Pharmacy, Anjaneri, Nashik-13, India

Abstract


Alzheimers disease very basically is characterized by the loss of the cognitive functions. β-amyloid is a major histopathological hallmark of Alzheimer's disease (AD). The disease is characterized by extracellular neuritic plaque composed of fibrillar-amyloid peptide and intracellular neurofibrillary tangles containing hyperphosphorylated tau. The peptides are generated by successive proteolysis of beta amyloid precursor protein, a large transmembrane glycoprotein that is initially cleaved by the site amyloid precursor protein cleaving enzyme -1 and subsequently by gamma secretase in the transmembrane domain. Retinoic acid is active metabolite of Vitamin A. Deprivation of Vitamin A results in amyloid-β accumulation, loss of hippocampal long term potentiation and memory deficit, all of which are hall mark of Alzheimers disease. Here we focused a role of retinoic acid on different pathophysiological features of Alzheimers disease. Retinoic acid may play an active role in treating neurodegenerative disorder. Retinoids appear to normalize many pathological states, and clinical side effects presently reported are mostly not serious except for retinoic acid syndrome.

Keywords


Alzheimers, Retinoic Acid, Vitamin A, Amyloid-β, Retinoid X Receptor(RXR).

References