• Archana Panche Birla Institute of Technology, Mesra, Ranchi,Jharkhand, India andMGM's Institute of Biosciences & Technology,Aurangabad, Maharashtra, India
  • Sheela Chandra Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
  • DIWAN AD MGM's Institute of Biosciences & Technology, Aurangabad, Maharashtra, India
  • Sanjay Harke MGM's Institute of Biosciences & Technology, Aurangabad, Maharashtra,India.




In recent past several efforts have been made to analyze the symptoms, causes, and cure of Alzheimer's disease (AD) and also to reveal biochemical
changes and pathogenesis of the brain affected with AD. Several studies indicated the main cause of the disease is deposition of necrotic β-amyloid
plaques in the brain. The enzymes β-secretase and γ-secretase catalyze the β-amyloid production. It has also been observed that the cells producing
acetylcholine, a major neurotransmitter, are destroyed by two closely related enzymes namely acetylcholinesterase (AChE) and butyrylcholinesterase
(BChE) in AD progression leading to cognitive disabilities. Hence, the research is going on in finding the inhibitors for these enzymes which will help
to either prolong or cure the AD. Discovering the inhibitors for AChE and BChE without side effects remains a major challenge as the AChE and BChE
inhibiting drugs available possess several side effects. Several new drugs are being discovered utilizing medicinal plant resources. Uses of flavonoids
as plant secondary metabolites are being tried for the treatment of AD. Efforts are being made to apply computational knowledge to streamline the
drug discovery process. Nevertheless, blood-brain barrier (BBB) permeation plays a vital role in drug discovery. BBB a physical barrier in the brain
through which the central nervous system therapeutic molecule has to permeate for its activity. Finding the potent lead candidates capable of crossing
the BBB remains to be a major challenge in neurodegenerative diseases. In the present review, attempts have been made to discuss on all these
important aspects.
Keywords: Alzheimer's disease, Amyloid precursor protein, β-amyloid, Blood-brain barrier, Flavonoids, Molecular docking, Multi-enzyme targeting.


Author Biographies

Archana Panche, Birla Institute of Technology, Mesra, Ranchi,Jharkhand, India andMGM's Institute of Biosciences & Technology,Aurangabad, Maharashtra, India

Asst.Prof., Department of Bioinformatics

Sheela Chandra, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.

Asst.Prof., Bio-engineering Department

DIWAN AD, MGM's Institute of Biosciences & Technology, Aurangabad, Maharashtra, India

Prof., MGM's Institute of Bioscineces & Technology

Sanjay Harke, MGM's Institute of Biosciences & Technology, Aurangabad, Maharashtra,India.

Director, MGM Institute of Biosciences & Technology


Anders W, Martin P. World Alzheimer Report 2010, The Global Economic Impact of Dementia. Alzheimers Disease International (ADI):21 September 2010, Reprinted June, 2011.

Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science 1982;215(4537):1237-9.

Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science 1984;225(4667):1168-70.

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30(4):572-80.

Sisodia SS, Price DL. Role of the beta-amyloid protein in Alzheimer’s disease. FASEB J 1995;9(5):366-70.

Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986;261:6084-9.

Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 1992;8(1):159-68.

Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: A major subunit of paired helical filaments and derivatized forms of normal Tau. Science 1991;251(4994):675-8.

Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985;82(12):4245-9.

Cecilia RA, Isabel C, Isabel G. Key Enzymes and Proteins in Amyloid-Β Production and Clearance, Alzheimer’s Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets. In: Suzanne M, editor. In Tech. Available from:β-production-and-clearance 2011.

Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325(6106):733‑6.

Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer’s disease. Mol Brain 2011;4:3.

Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120(3):885-90.

Roher A, Wolfe D, Palutke M, KuKuruga D. Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proc Natl Acad Sci U S A 1986;83(8):2662-6.

Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, et al. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o). Nature 1993;362(6419):75-9.

Asai M, Hattori C, Szabó B, Sasagawa N, Maruyama K, Tanuma S, et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun 2003;301(1):231-5.

Postina R. A closer look at alpha-secretase. Curr Alzh Res 2008:5(2):179-86.

Zhang C, Saunders AJ. Therapeutic targeting of the alpha-secretase pathway to treat Alzheimer’s disease. Discov Med 2007;7(39):113-7.

Luo X, Yan R. Inhibition of BACE1 for therapeutic use in Alzheimer’s disease. Int J Clin Exp Pathol 2010;3(6):618-28.

Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001;4(3):231-2.

Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: Implications for Alzheimer’s disease therapeutics. Hum Mol Genet 2001;10(12):1317-24.

Cole SL, Vassar R. The Alzheimer’s disease beta-secretase enzyme, BACE1. Mol Neurodegener 2007;2:22.

Haapasalo A, Kovacs DM. The many substrates of presenilin/γ-secretase. J Alzheimers Dis 2011;25(1):3-28.

Kimberly WT, Wolfe MS. Identity and function of gamma-secretase. J Neurosci Res 2003;74(3):353-60.

Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003;422(6930):438-41.

Zhang Y, Pardridge WM. Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke 2001;32(6):1378-84.

Khan MT. Molecular interactions of cholinesterases inhibitors using in silico methods: Current status and future prospects. N Biotechnol 2009;25(5):331-46.

Saklani A, Kutty SK. Plant-derived compounds in clinical trials. Drug Discov Today 2008;13(3-4):161-71.

Mehta M, Adem A, Sabbagh M. New acetylcholinesterase inhibitors for Alzheimer’s disease. Int J Alzheimers Dis 2012;2012:728983.

García-Ayllón MS, Small DH, Avila J, Sáez-Valero J. Revisiting the role of acetylcholinesterase in Alzheimer’s disease: Cross-talk with P-tau and ß-Amyloid. Front Mol Neurosci 2011;4:22.

McGleenon BM, Dynan KB, Passmore AP. Acetylcholinesterase inhibitors in Alzheimer’s disease. Br J Clin Pharmacol 1999;48(4):471‑80.

Massoulié J, Pezzementi L, Bon S, Krejci E, Vallette FM. Molecular and cellular biology of cholinesterases. Prog Neurobiol 1993;41(1):31‑91.

Eskander MF, Nagykery NG, Leung EY, Khelghati B, Geula C. Rivastigmine is a potent inhibitor of acetyl-and butyrylcholinesterase in Alzheimer’s plaques and tangles. Brain Res 2005;1060(1-2):144-52.

Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: An updated meta-analysis. J Neural Transm 2009;116(4):457-65.

Clark DE. In silico prediction of blood-brain barrier permeation. DrugDiscov Today 2003;8(20):927-33.

Cohen Z, Ehret M, Maitre M, Hamel E. Ultrastructural analysis of tryptophan hydroxylase immunoreactive nerve terminals in the rat cerebral cortex and hippocampus: Their associations with local blood vessels. Neuroscience 1995;66(3):555-69.

Paspalas CD, Papadopoulos GC. Ultrastructural relationships between noradrenergic nerve fibers and non-neuronal elements in the rat cerebral cortex. Glia 1996;17(2):133-46.

Grieb P, Forster RE, Strome D, Goodwin CW, Pape PC. O2 exchange between blood and brain tissues studied with 18O2 indicator-dilution technique. J Appl Physiol 1985;58(6):1929-41.

Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem 1985;44(6):1771-8.

Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: An overview: Structure, regulation, and clinical implications. Neurobiol Dis 2004;16(1):1-13.

Finkel SI. Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin Ther 2004;26(7):980-90.

Stuchbury G, Münch G. Alzheimer’s associated inflammation, potential drug targets and future therapies. J Neural Transm 2005;112(3):429-53.

Tabet N. Acetylcholinesterase inhibitors for Alzheimer’s disease: Anti-inflammatories in acetylcholine clothing. Age Ageing 2006;35(4):336‑8.

Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G. Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem 2005;280(40):34202-9.

Mentenopoulos G. Recent advances in the pharmacotherapy of Alzheimer’s disease. Ann Gen Hosp Psychiatry 2001;2(1):S22.

Lahiri DK, Farlow MR, Greig NH, Sambamurti K. Current drug targets for Alzheimer’s disease treatment. Drug Dev Res 2002;56:267-81.

Tumiatti V, Minarini A, Bolognesi ML, Milelli A, Rosini M, Melchiorre C. Tacrine derivatives and Alzheimer’s disease. Curr Med Chem 2010;17(17):1825-38.

Jacobson SA, Sabbagh MN. Donepezil: Potential neuroprotective and disease-modifying effects. Expert Opin Drug Metab Toxicol 2008;4(10):1363-9.

Tomich CH, da Silva P, Carvalho I, Taft CA. Homology modeling and molecular interaction field studies of alpha-glucosidases as a guide to structure-based design of novel proposed anti-HIV inhibitors. J Comput Aided Mol Des 2005;19(2):83-92.

Oprea TI. In Chemoinformatics in Drug Discovery. In: Mannhold R, Kubinyi H, Timmerman H. Methods and principles in medicinal chemistry. Weinheim: Wiley-VCH; 2005. p. 493-04.

Schneider G, Fechner U. Computer-based de novo design of drug-like molecules. Nat Rev Drug Discov 2005;4(8):649-63.

Khandelwal A, Lukacova V, Comez D, Kroll DM, Raha S, Balaz S. A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands. J Med Chem 2005;48(17):5437-47.

Gupta S, Pandey A, Tyagi A, Mohan GA. Computational analysis of Alzheimer’s disease drug targets. Curr Res Inf Pharm Sci 2010;11(1):1‑10.

da Silva CH, Campo VL, Carvalho I, Taft CA. Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer’s disease. J Mol Graph Model 2006;25(2):169‑75.

Camps P, El Achab R, Morral J, Muñoz-Torrero D, Badia A, Baños JE, et al. New tacrine-huperzine A hybrids (huprines): Highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer’s disease. J Med Chem 2000 30;43:4657-66.

Correa-Basurto J, Flores-Sandoval C, Marín-Cruz J, Rojo-Domínguez A, Espinoza-Fonseca LM, Trujillo-Ferrara JG. Docking and quantum mechanic studies on cholinesterases and their inhibitors. Eur J Med Chem 2007;42:10-9.

Rodney C, Toni MK, Norman GL, Buchanan B, Gruissem W, Jones R. Natural Products (Secondary Metabolites). In: Buchanan B, Gruissem W, Jones R. Biochemistry & Molecular Biology of Plants. American Society of Plant Physiologists. 2000. p. 1250-18.

Narayana KR, Reddy MS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol 2001:33:2-16.

Anand S. Various approaches for secondary metabolite production through plant tissue culture. Pharmacia 2010:1:1-7.

Dastmalchi K, Dorman HJ, Vuorela H, Hiltunen R. Plants as potential sources for drug development against Alzheimer’s disease. Int J Biomed Pharm Sci 2007:1(2):83-104.

Jäger AK, Saaby L. Flavonoids and the CNS. Molecules 2011;16(2):1471-85.

Shen Y, Zhang J, Sheng R, Dong X, He Q, Yang B, Hu Y. Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors. J Enzyme Inhibition Med Chemistry 2009:24(2):372-80.

Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Flavonols and flavones as BACE-1 inhibitors: Structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim Biophys Acta 2008;1780(5):819-25.

Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A. Multitarget drugs of plants origin acting on Alzheimer’s disease. Curr Med Chem 2013;20(13):1686-93.

Azam F, Amer AM, Abulifa AR, Elzwawi MM. Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: A computational investigation. Drug Des Devel Ther 2014;8:2045-59.



How to Cite

Panche, A., S. Chandra, DIWAN AD, and S. Harke. “ALZHEIMER’S AND CURRENT THERAPEUTICS: A REVIEW”. Asian Journal of Pharmaceutical and Clinical Research, vol. 8, no. 3, May 2015, pp. 14-19,



Review Article(s)