50
Views
23
CrossRef citations to date
0
Altmetric
Review

Emerging therapeutics for Alzheimer’s disease

, &
Pages 695-704 | Published online: 10 Jan 2014

References

  • Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neuro2, 539–547 (2003).
  • Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science297, 353–356 (2002).
  • Esiri MM. The neuropathology of Alzheimer’s disease. In: Neurobiology of Alzheimer’s disease. Dawbarn D, Allen SJ (Eds), Oxford University Press, UK 33–53 (2001).
  • Hussain I. The potential for BACE1 inhibitors in the treatment of Alzheimer's disease. Drugs7, 653–658 (2004).
  • Luo Y, Bolon B, Kahn S et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci.4, 231–232 (2001).
  • Wong HK, Sakurai T, Oyama F et al. β subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J. Biol. Chem.280, 23009–23017 (2005).
  • von Arnim CA, Kinoshita A, Peltan ID et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J. Biol. Chem.280, 17777–17785 (2005).
  • Pangalos MN, Jacobsen SJ, Reinhart PH. Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the β-amyloid peptide. Biochem. Soc. Trans.33, 553–558 (2005).
  • Xie J, Guo Q. PAR-4 is involved in regulation of β-secretase cleavage of the Alzheimer amyloid precursor protein. J. Biol. Chem.280, 13824–13832 (2005).
  • He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R. Reticulon family members modulate BACE1 activity and amyloid-β peptide generation. Nat. Med.10, 959–965 (2004).
  • Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies. Proc. Natl Acad. Sci. USA102, 7718–7723 (2005).
  • Selkoe DJ, Schenk D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Ann. Rev. Pharmacol. Toxicol43, 545–584 (2003).
  • Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease. Int. J. Biochem. Cell Biol.35, 1505–1535 (2003).
  • Medina M, Dotti CG. Ripped out by presenilin-dependent γ-secretase. Cell Signal.15, 829–841 (2003).
  • Koo EH, Kopan R. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nat. Med.10(Suppl.) S26–S33 (2004).
  • Wong HK, Sakurai T, Oyama F et al. β subunits of voltage-gated sodium channels are novel substrates of BACE1 and γ-secretase. J. Biol. Chem.280, 23009–23017 (2005).
  • Maretzky T, Schulte M, Ludwig A et al. L1 is sequentially processed by two differently activated metalloproteases and presenilin/γ-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol. Cell Biol.25, 9040–9053 (2005).
  • Cai J, Jiang W, Grant MB, Boulton M. Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of VEGFR-1. J. Biol. Chem.281(6), 3604–3613 (2005).
  • Nunan J, Small DH. Regulation of APP cleavage by α-, β- and γ-secretases. FEBS Lett.483, 6–10 (2000).
  • Siemers E, Skinner M, Dean RA et al. Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin. Neuropharmacol28, 126–132 (2005).
  • Netzer WJ, Dou F, Cai D et al. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc. Natl Acad. Sci. USA100, 12444–12449 (2003).
  • Petit A, Pasini A, Alves DC et al. JLK isocoumarin inhibitors: selective γ-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. J. Neurosci. Res.74, 370–377 (2003).
  • Beher D, Clarke EE, Wrigley JD et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site. Evidence for an allosteric mechanism. J. Biol. Chem.279, 43419–43426 (2004).
  • Weggen S, Eriksen JL, Das P et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature414, 212–216 (2001).
  • Doraiswamy PM, Xiong GL. Pharmacological strategies for the prevention of Alzheimer's disease. Expert Opin. Pharmacother.7, 1–10 (2006).
  • Hooper NM. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein. Biochem. Soc. Trans.33, 335–338 (2005).
  • Postina R, Schroeder A, Dewachter I et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest.113, 1456–1464 (2004).
  • Hooper NM, Turner AJ. The search for α-secretase and its potential as a therapeutic approach to Alzheimer’s disease. Curr. Med. Chem.9, 1107–1119 (2002)
  • Abad-Rodriguez J, Ledesma MD, Craessaerts K et al. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J. Cell Biol.167, 953–960 (2004).
  • Shobab LA, Hsiung GY, Feldman HH. Cholesterol in Alzheimer's disease. Lancet Neurol.4, 841–852 (2005).
  • MRC/BHF. Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet360, 7–22 (2002).
  • Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet360, 1623–1630 (2002).
  • Sparks DL, Sabbagh MN, Connor DJ et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch. Neurol.62, 753–757 (2005).
  • Kojro E, Fahrenholz F. The nonamyloidogenic pathway: structure and function of α-secretases. Subcell. Biochem.38, 105–127 (2005).
  • Amantea D, Russo R, Bagetta G, Corasaniti MT. From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. Pharmacol. Res.52, 119–132 (2005).
  • Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience101, 485–512 (2000).
  • Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA289, 2651–2662 (2003).
  • Mulnard RA, Cotman CW, Kawas C et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA283, 1007–1015 (2000).
  • Henderson VW, Paganini-Hill A, Miller BL et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology54, 295–301 (2000).
  • Wang PN, Liao SQ, Liu RS et al. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology54, 2061–2066 (2000).
  • Zimmermann M, Gardoni F, Marcello E et al. Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. J. Neurochem.90, 1489–1499 (2004).
  • Iwata N, Tsubuki S, Takaki Y et al. Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med.6, 143–150 (2000).
  • Farris W, Mansourian S, Chang Y et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl Acad. Sci USA100, 4162–4167 (2003).
  • Leissring MA, Farris W, Chang AY et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron40, 1087–1093 (2003).
  • Eckman EA, Reed DK, Eckman CB. Degradation of the Alzheimer's amyloid β peptide by endothelin-converting enzyme. J. Biol. Chem.276, 24540–24548 (2001).
  • Marr RA, Guan H, Rockenstein E et al. Neprilysin regulates amyloid β peptide levels. J. Mol. Neurosci.22, 5–11 (2004).
  • Eckman EA, Eckman CB. Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochem. Soc. Trans.33, 1101–1105 (2005).
  • Saito T, Iwata N, Tsubuki S et al. Somatostatin regulates brain amyloid β peptide Aβ(42) through modulation of proteolytic degradation. Nat. Med.11, 434–439 (2005).
  • Song ES, Mukherjee A, Juliano MA et al. Analysis of the subsite specificity of rat insulysin using fluorogenic peptide substrates. J. Biol. Chem.276, 1152–1155 (2001).
  • Song ES, Juliano MA, Juliano L and Hersh LB. Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development. J. Biol. Chem.278, 49789–49794 (2003).
  • Cleary JP, Walsh DM, Hofmeister JJ et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat. Neurosci.8, 79–84 (2005).
  • Lesne S, Koh MT, Kotilinek L et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature440, 352–357 (2006).
  • Citron M. Strategies for disease modification in Alzheimer's disease. Nat. Rev. Neurosci.5, 677–685 (2004).
  • Permanne B, Adessi C, Saborio GP et al. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a β-sheet breaker peptide. FASEB J.16, 860–862 (2002).
  • Evin G, Weidemann A. Biogenesis and metabolism of Alzheimer's disease Aβ amyloid peptides. Peptides23, 1285–1297 (2002).
  • Geerts H. NC-531 (Neurochem). Curr. Opin. Investig. Drugs5, 95–100 (2004).
  • Ritchie CW, Bush AI, Mackinnon A et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot Phase 2 clinical trial. Arch. Neurol.60, 1685–1691 (2003).
  • Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature400, 173–177 (1999).
  • Bard F, Cannon C, Barbour R et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med.6, 916–919 (2000).
  • Bard F, Barbour R, Cannon C et al. Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc. Natl Acad. Sci. USA100, 2023–2028 (2003).
  • Racke MM, Boone LI, Hepburn DL et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid β. J. Neurosci.25, 629–636 (2005).
  • Janus C, Pearson J, McLaurin J et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature408, 979–982 (2000).
  • Morgan D, Diamond DM, Gottschall PE et al. A β peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature408, 982–985 (2000).
  • Schenk D. Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning. Nat. Rev. Neurosci.3, 824–828 (2002).
  • Orgogozo JM, Gilman S, Dartigues JF et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology61, 46–54 (2003).
  • Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med.9, 448–452 (2003).
  • Ferrer I, Boada RM, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease. Brain Pathol.14, 11–20 (2004).
  • Masliah E, Hansen L, Adame A et al. Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology64, 129–131 (2005).
  • Hock C, Konietzko U, Streffer JR et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron38, 547–554 (2003).
  • Fox NC, Black RS, Gilman S et al. AN1792(QS-21)-201 Study. Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology64, 1563–1572 (2005).
  • Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid β-peptide clearance through transport across the blood–brain barrier. Stroke35, 2628–2631 (2004).
  • LaFerla FM, Oddo S. Alzheimer's disease: Aβ, tau and synaptic dysfunction. Trends Mol. Med.11, 170–176 (2005).
  • Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology42, 631–639 (1992).
  • Oddo S, Caccamo A, Shepherd JD et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron39, 409–421 (2003).
  • Lau LF, Schachter JB, Seymour PA, Sanner MA. Tau protein phosphorylation as a therapeutic target in Alzheimer's disease. Curr. Top. Med. Chem.2, 395–415 (2002).
  • Cohen P, Goedert M. GSK3 inhibitors: development and therapeutic potential. Nat. Rev. Drug Discov.3, 479–487 (2004).
  • Monaco EA III. Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease. Curr. Alzheimer Res.1, 33–38. (2004).
  • Takashima A, Murayama M, Murayama O et al. Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc. Natl Acad. Sci. USA95, 9637–9641 (1998).
  • Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron43, 321–332 (2004).
  • Zhang B, Maiti A, Shively S et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl Acad. Sci USA.102, 227–231 (2005).
  • Akiyama H, Barger S, Barnum S et al. Inflammation and Alzheimer's disease. Neurobiol. Aging21, 383–421 (2000).
  • Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis. Assoc. Disord.14(Suppl. 1), S47–S53 (2000).
  • Moore AH, O'Banion MK. Neuroinflammation and anti-inflammatory therapy for Alzheimer's disease. Adv. Drug Deliv. Rev.54, 1627–1656 (2002).
  • Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J.19, 1592–1601 (2005).
  • Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology53, 197–201 (1999).
  • Aisen PS, Schafer KA, Grundman M et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA289, 2819–2826 (2003).
  • Reines SA, Block GA, Morris JC et al. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology62, 66–71 (2004).
  • Couzin J. Clinical trials. Halt of Celebrex study threatens drug's future, other trials. Science306, 2170 (2004).
  • Aisen PS, Davis KL, Berg JD et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's disease cooperative study. Neurology54, 588–593 (2000).
  • Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ. Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet358, 455–460 (2001).
  • Heneka MT, Sastre M, Dumitrescu-Ozimek L et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice. Brain128, 1442–1453 (2005).
  • Watson GS, Cholerton BA, Reger MA et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am. J. Geriatr. Psychiatry13, 950–958 (2005).
  • Risner ME, Saunders AM, Altman JF et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J.(2006) [Epub ahead of print].
  • DeKosky ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J. Am. Geriatr. Soc.51, S314–S320 (2003).

Websites

  • Clincial trials.gov. www.clinicaltrials.gov/ct/show/NCT00244322?order=1. Accessed 18 January, 2006.
  • Clincial trials.gov. www.clinicaltrials.gov/ct/show/NCT00087724. Accessed 30 November, 2005.
  • Alzheimer research forum. www.alzforum.org/drg/drc/detail.asp?id=84 Accessed 30 November, 2005.
  • Clincial trials.gov. www.clinicaltrials.gov/ct/show/NCT00088387. Accessed 30 November, 2005.
  • Alzheimer research forum. www.alzforum.org/dis/tre/drc/detail.asp?id=64. Accessed 1 December, 2005.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.