The bright future of Alzheimer’s disease pharmacotherapy

Jimma L. Lenjisa, Gizaw D. Satessa, Minyahil A. Woldu


Alzheimer's disease (AD) is the most common cause of progressivedementia in the elderly population leading to progressive disturbances of cognitivefunctions. It is the disease whose prevalence is rising but with very limited numbers of drugs limiting its progression making more difficult to overcome the evil side of this disease. Currently, there are a number of drugs in pipeline blooming the hope to effectively modify the progression of AD. All of these newer agents are directing toward the biochemical mechanism of AD development including targeting tau protein (e.g. Inhibition of taukinase), 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 on which the discovery of these newer agents based in addition to giving a clear picture on these agents.


Alzheimer's disease, Secretase inhibitors, Gene therapy, Stem cell therapy

Full Text:



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

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. 2007June;5(2):127–34.

Jacobsen J. S, Reinhart P, and Pangalos M. N. Current Concepts in Therapeutic Strategies Targeting Cognitive Decline and Disease Modification in Alzheimer’s disease. Neuro Rx. 2005;2(4):612–26.

Perl D. P. Neuropathology of Alzheimer’s disease. Mt Sinai J Med. 2010;77:32–42.

Christensen, D.D. changing the course of Alzheimer’s disease: Anti-Amyloid Disease-Modifying Treatments on Horizon. Prim Care Companion J Clin Psychiatry. 2007;9:32-41.

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

Michaelis M.R. Drugs Targeting Alzheimer's Disease: Some Things Old and Some Things New. JPET. 2003;304(3):897-904.

Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–8,discussion:278–84.

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.

Kryger G, Silman I, Sussman JL. Three-dimensional structure of a complex of E2020 with acetylcholinesterase from Torpedo californica. J Physiol (Lond) Paris. 1998;92:191–4.

Farlow M. A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatrics. 2002;1:93–126.

Wolfe MS. Secretase inhibitors as molecular probes of presenilin function. J Mol Neurosci. 2001;17:199–204.

Kopan R and Goate A. A common enzyme connects Notch signaling and Alzheimer’s disease. Genes. 2000;14:2799–2806.

Golde, TE, Younkin, SG. Presenilins as therapeutic targets for the treatment of Alzheimer’s disease. Trends Mol. Med. 2001;7:264-9.

Dovey, H, Varghese, J, Anderson, JP. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in the brain. J. Neurochem. 2000;76:1-10.

De Strooper B et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518-22.

Yankner, BA et al. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science. 1989;245:417-20.

Serneels L, Dejaegere T, and Craessaerts K. et al. Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci. U S A. 2005;102:1719–24.

Barten DM, Guss VL, and Corsa JA. et al. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharmacol Exp Ther. 2005;312:635–43.

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.

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.

Kurochkin IV, Goto S. Alzheimer’s β-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994;345:33–7.

Mukherjee A, Song E, Kihiko-Ehmann M, Goodman JP Jr, Pyrek JS, Estus S, et al. Insulysin hydrolyzes amyloid β peptides to products that are neither neurotoxic nor deposit on amyloid plaques. J Neurosci. 2000;20:8745–9.

Bertram L, Tanzi RE. Alzheimer’s disease: one disorder, too many genes? Hum Mol Genet. 2004Apr1;13SpecNo1:R135-41.

Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM. Age- and region-dependent alterations in Aβ-degrading enzymes: implications for Aβ-induced disorders. Neurobiol Aging. 2005;26:645–54.

Carson JA, Turner AJ. β-Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases? J Neurochem. 2002;81:1–8.

Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, et al. Identification of the major Aβ1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000;6:143–50.

Marr RA, Rockenstein E, Mukherjee A, Kindy MS, Hersh LB, Gage FH, et al. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23: 1992–1996, 2003.

Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, et al. Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation. Nat Med. 2005;11:434–9.

Periz G, Fortini ME. Proteolysis in Alzheimer’s disease. Can plasmin tip the balance? EMBO. 2001Jan;1(6):477-8.

Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, et al. The plasmin system is induced by and degrades amyloid-β aggregates. J Neurosci. 2000;20:3937–46.

Tucker HM, Kihiko-Ehmann M, Wright S, Rydel RE, Estus S. Tissue plasminogen activator requires plasminogen to modulate amyloid-β neurotoxicity and deposition. J Neurochem. 2000;75:2172–7.

Tsirka SE, Rogove AD, Bugge TH, Degen JL, Strickland S. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci. 1997;17:543–52.

Gervais F, Chalifour R, and Garceau D. et al. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid. 2001;8suppl1:28–35.

Rattray M.. Technology evaluation: colostrinin, ReGen. Curr Opin Mol Ther. 2005;7:78–84.

Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, et al. Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998;273:12817-26.

Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001;30:665-76.

Weksler ME. The immunotherapy of Alzheimer’s disease. Immun Ageing. 2004;1:2.

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.

Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D. Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol. 2003;33:3232–41.

Lombardo JA, Stern EA, Mclellan ME, Kajdasz ST, Hickey GA, Bacskai BJ, Hyman BT. βAmyloid-antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci. 2003;23:10879–83.

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–7.

Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916–9.

Solomon B, Koppel R, Frankel D, Hanan-Aharon E. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci. USA. 1997;94:4109–12.

DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci. USA. 2001;98:8850–5.

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.

Tsai LH, Lee MS, Cruz J. Cdk5, a therapeutic target for Alzheimer’s disease? Biochimica et Biophysica Acta. 2004;1697:137–42.

Bhat RV, Budd Haeberlein SL, Avila J. Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem. 2004;89:1313–7.

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.

Mandelkow EM, Mandelkow E. Tau in Alzheimer's disease. Trends Cell Biol. 1998;8:425-7.

Li L, Sengupta A, Haque N, Grundke-Iqbal I, Iqbal K. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett. 2004;566:261-9.

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.

Hughes IA. A perspective on stem cells by a clinician. Eur J Endocrinol. 2004;151(Suppl 3):U3–5.

Tanne JH. Activating stem cells may treat Alzheimer’s. BMJ. 2005;330:622.