Novel therapies for treatment of Alzheimer’s Disease

Manali Mangesh Mahajan, Sujata M. Dudhgaonkar, Swapnil Narayan Deshmukh


Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly population. It is a chronic neurodegenerative disease associated with the loss of nerve cells in areas of the brain that are vital to memory and other mental abilities. Currently available treatments for AD: such as reversible anticholinesterases namely tacrine, donepezil, rivastigmine, galantamine and NMDA receptor antagonists like memantine provide largely symptomatic relief with only minor effects on the course of the disease. There are a number of newer drugs to effectively modify the progression of AD. All of these newer agents are directing towards the biochemical mechanism of AD development, including targeting tau protein (e.g. Inhibition of tau kinase), targeting Aβ (e.g. β-Secretase Inhibitors), and therapies involving gene as well as stem cell strategies. Hence in this review, we summarized the pathogenesis of AD along with the future targets of therapy.



Alzheimer's disease, Tau protein, amyloid beta plaques, secretase enzyme

Full Text:




Berrios G E (1991) Alzheimer’s Disease: A Conceptual History. International Journal of Geriatric Psychiatry 5: 355-365

Hans-Wolfgang Klafki, Matthias Staufenbiel, Johannes Kornhuber and Jens Wiltfang. Therapeutic approaches to Alzheimer's disease. Brain. 2006; 129 (11):2840-55.

Standaert D.G, Roberson E.R; Treatment of Central Nervous System degenerative disorders. Goodman and Gilman’s. The Pharmacological Basis of Therapeutics. 12th Edition, Chapter 22. New York: McGraw Hill; 2011: 619-622.

Sharma HL, Sharma KK, Drug therapy for neurodegenerative disorders; Principles of Pharmacology; 2nd edition; Chapter 40;2013: 540-542.

Thomas Wisniewski and Allal Boutajangout. Vaccination as a Therapeutic Approach to Alzheimer’s disease. Mount Sinai Journal of Medicine. 2010; 77: 17-31.

Chen S, Zhang XJ, Li L, and Le WD. Current Experimental Therapy for Alzheimer’s disease. Curr Neuropharmacol. 2007 June; 5(2):127–34.

Hernández F, Avila J. "Tauopathies". Cell. Mol. Life Sci. 2007; 64 (17):2219–33.

Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M et al. Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci. USA. 1999; 96:3922–7.

Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives

stimulated by activation of muscarinic acetylcholine receptors. Science. 1992;258:304–7.

Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer's disease. Lancet368:387–403.

Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH (2007). "Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals".Alzheimer Disease and Associated Disorders 21 (4): 292–9.

Bartus RT, Dean RL 3rd, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–14.

Davies P, Maloney AJ. 1976. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet. 1976Dec25;2(8000):1403.

Soto C, Kindy MS, Baumann M, Frangione B. Inhibition of Alzheimer’s amyloidosis by peptides that prevent beta-sheet conformation. Biochem Biophys Res Commun. 1996;226:672–80.

Chacon MA, Barria MI, Soto C, Inestrosa NC. Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry. 2004;9:953–61.

Strozyk D, Launer LJ, Adlard PA et al. (2007). "Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid". Neurobiol Aging 30 (7): 1069-77.

Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A. Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron. 2003;38:547–54.

Gelinas DS, Salilva K, Fenili D, George-Hyslop P, Mclaurin J. Immunotherapy for Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101:14657–62.

The Good news on Antiamyloid Alzheimer’s Therapies,NEJM,1/2014,370-378

Whitfield JF (2007). "The road to LOAD: late-onset Alzheimer's disease and a possible way to block it". Expert Opinion on Therapeutic Targets 11 (10): 1257–1260.

Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ (2007). "Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease". Neurology 69 (9): 878–85.

Benito C, Núñez E, Pazos MR, Tolón RM, Romero J (August 2007). "The endocannabinoid system and Alzheimer's disease". Mol Neurobiol 36 (1): 75–81.

Campbell VA, Gowran A (November 2007). "Alzheimer's disease; taking the edge off with cannabinoids?". Br J Pharmacol 152 (5): 655–62.

Eubanks LM, Rogers CJ, Beuscher AE 4th, Koob GF, Olson AJ, Dickerson TJ, Janda KD (Nov–Dec 2006). "A molecular link between the active component of marijuana and Alzheimer's disease pathology.". Mol Pharm 3 (6): 773–777.

Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, de Pooter T, de Rijk P, Del-Favero J, van Broeckhoven C. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet. 2005;14:1753–62.

Michaelis ML. Drugs targeting Alzheimer’s disease: some things old and some things new. J Phar. macol Exp Ther. 2003;304:897–904.

Li X, Lu F, Tian Q, Yang Y, Wang Q, Wang JZ. Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture. J Neural Transm. 2005;113(1):93–102.

Drewes G. Marking tau for tangles and toxicity. Trends Biochem Sci. 2004;29:548–55.

Iqbal K, Grundke-Iqbal I. Inhibition of neurofibrillary degeneration: a promising approach to Alzheimer’s disease and other tauopathies. Curr Drug Targets. 2004;5:495–502.

Bulic, B; Pickhardt, M; Schmidt, B; Mandelkow, EM; Waldmann, H; Mandelkow, E (2009). "Development of tau aggregation inhibitors for Alzheimer's disease". Angewandte Chemie (International ed. in English) 48(10): 1740–52.

Lermontova, N. N., Redkozubov, A. E., Shevtsova, E. F., Serkova, T. P., Kireeva, E. G., Bachurin, S. O. (Nov 2001). "Dimebon and Tacrine Inhibit Neurotoxic Action of b-Amyloid in Culture and Block L-type Ca2+ Channels".Bulletin of Experimental Biology and Medicine 132 (5): 1079–1083.

Grigor'ev V. V., Dranyi O. A., Bachurin S. O. (Nov 2003). "Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons". Bulletin of Experimental Biology and Medicine 136 (5): 474–477.

BACHURIN, S. O., SHEVTSOVA, E. P., KIREEVA, E. G., OXENKRUG, G. F. and SABLIN, S. O. (May 2003). "Mitochondria as a Target for Neurotoxins and Neuroprotective Agents". Annals of the New York Academy of Sciences 993: 334–344.

Wu J., Li Q., Bezprozvanny I. (Oct 2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration 3: 15.

Braddock M. Safely slowing down the decline in Alzheimer’s disease: gene therapy shows potential. Expert Opin Investig Drugs. 2005;14:913–5.

Siemer E, Skinner M, Dean RA, Conzales C, Satterwhite J, Farlow M, Ness D, May PC. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol. 2005;28:126–32.

Alzheimer's & Dementia: The Journal of the Alzheimer's Association Volume 10, Issue 5, Pages 571–581, September 2014.

Weiss, S., Dunne, C., Hewson, J., et al. (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J. Neurosci. 16, 7599–7609.

Carpenter, M.K., Cui, X., Hu, Z.Y., et al. (1999) In vitro expansion of a multipotent population of human neural progenitor cells. Exp. Neurol. 158, 265–278

Dr. Ulrich Werth Makes a Good Point; Journal of Longevity ;2008 ;Vol. 14 / No. 2

Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K: Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull 2003, 61(3):255-60.

Tancredi V, D'Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, Eusebi F: Tumor necrosis factor alters synaptic transmission in rat hippocampal slices.Neurosci Lett 146(2):176-8.1992 Nov 9

Halassa MM, Fellin T, Haydon PG: The tripartite synapse: roles for gliotransmission in health and disease.Trends Mol Med 2007, 13(2):54-63.

Turrigiano GG, Nelson SB: Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci 2004, 5(2):97-107.

Wozniak M, Mee A, Itzhaki R (2008). "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques". J Pathol 217 (1): 131–138.

Choi Y, Kim HS, Shin KY et al. (November 2007). "Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models". Neuropsychopharmacology 32 (11): 2393–2404.

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (June 2004)."Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning". Eur. J. Neurosci. 19 (12): 3305–16.

Khlistunova I, Biernat J, Wang Y et al. (January 2006). "Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs". J. Biol. Chem. 281 (2): 1205–1214.

Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS (2005). "Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study". Am J Geriatr Psychiatry 13(11): 950–958.

Risner ME, Saunders AM, Altman JFB, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD (2006). "Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease".Pharmacogenomics J 6 (4): 246–254.

Brodbeck J, Balestra M, Saunders A, Roses A, Mahley R, Huang Y (2008)."Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons". Proceedings of the National Academy of Sciences of the United States of America 105 (4): 1343–1346.

Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. Freiherr J1, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. CNS Drugs. 2013 Jul;27(7):505-14.

Marx, C, Trost, W, Shampine, L, Stevens, R, Hulette, C, Steffens, D, Ervin, J, Butterfield, M et al. (December 2006). "The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer's Disease". Biological Psychiatry 60(12): 1287–94.

Wang, JM, Singh, C, Liu, L, Irwin, RW, Chen, S, Chung, EJ, Thompson, RF, Brinton, RD. (2010). "Allopregnanolone reverses neuron and cognitive deficits in a mouse model of Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America 107 (14): 6498–6503.


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


  • There are currently no refbacks.

Copyright (c) 2015 International Journal of Pharmacological Research

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.