Skip to main content

Cdk5 as a Drug Target for Alzheimer’s Disease

Abstract

Neurofibrillary tangles (NFTs) are a pathological hallmark in the Alzheimer’s disease (AD) brain and are well correlated with progression of the disease. Since NFTs consist mainly of hyperphosphorylated tau, tau kinases have been suggested as drug targets to slow the progression of AD. This notion has further been supported by recent studies showing the importance of tau and its phosphorylation in neurodegeneration and cognitive deficits in animal models. Among the different putative tau kinases, cyclin-dependent kinase 5 (Cdk5) remains an appealing drug target for AD. Activation of Cdk5 in animal models recapitulates many AD features including tau hyperphosphorylation, NFTs, neurodegeneration, cognitive impairments, and increase in Aβ levels. In addition, inhibition of Cdk5 activities is neuroprotective and appears to enhance long-term potentiation and improve learning and memory—all are potential beneficial features for the treatment of AD.

Keywords

  • Amyloid Precursor Protein
  • Morris Water Maze
  • Cdk5 Inhibitor
  • Retinal Degeneration
  • Amyloid Precursor Protein Processing

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-0-387-78887-6_18
  • Chapter length: 17 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   149.00
Price excludes VAT (USA)
  • ISBN: 978-0-387-78887-6
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   199.99
Price excludes VAT (USA)
Hardcover Book
USD   199.99
Price excludes VAT (USA)

References

  • Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE, Nelson RB, McNeish JD (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci USA 97:2910–2915.

    PubMed  CAS  Google Scholar 

  • Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA 98:6923–6928.

    PubMed  CAS  Google Scholar 

  • Alvarez A, Toro R, Caceres A, Maccioni RB (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 459:421–426.

    PubMed  CAS  Google Scholar 

  • Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446–5454.

    PubMed  CAS  Google Scholar 

  • Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99:353–370.

    PubMed  CAS  Google Scholar 

  • Angelo M, Plattner F, Irvine EE, Giese KP (2003) Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur J Neurosci 18:423–431.

    PubMed  Google Scholar 

  • Augustinack JC, Sanders JL, Tsai LH, Hyman BT (2002) Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles. J Neuropathol Exp Neurol 61:557–564.

    PubMed  CAS  Google Scholar 

  • Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662.

    PubMed  CAS  Google Scholar 

  • Bian F, Nath R, Sobocinski G, Booher RN, Lipinski WJ, Callahan MJ, Pack A, Wang KK, Walker LC (2002) Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. J Comp Neurol 446:257–266.

    PubMed  CAS  Google Scholar 

  • Bu B, Li J, Davies P, Vincent I (2002) Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 22:6515–6525.

    PubMed  CAS  Google Scholar 

  • Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, Nusinowitz S, Rengarajan K, Boyd AP, Sidney SS, Phillips MJ, Stewart RE, Chaudhury R, Nickerson JM, Heckenlively JR, Boatright JH (2007) Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vision Res 47:624–633.

    PubMed  CAS  Google Scholar 

  • Cheung ZH, Fu AK, Ip NY (2006) Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50:13–18.

    PubMed  CAS  Google Scholar 

  • Crespo-Biel N, Canudas AM, Camins A, Pallas M (2007) Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. Neurochem Int 50:435–442.

    PubMed  CAS  Google Scholar 

  • Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26:10536–10541.

    PubMed  CAS  Google Scholar 

  • Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483.

    PubMed  CAS  Google Scholar 

  • Engel T, Goni-Oliver P, Lucas JJ, Avila J, Hernandez F (2006a) Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 99:1445–1455.

    CAS  Google Scholar 

  • Engel T, Lucas JJ, Gomez-Ramos P, Moran MA, Avila J, Hernandez F (2006b) Cooexpression of FTDP-17 tau and GSK-3beta in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol Aging 27:1258–1268.

    CAS  Google Scholar 

  • Evans DB, Rank KB, Bhattacharya K, Thomsen DR, Gurney ME, Sharma SK (2000) Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau's ability to promote microtubule assembly. J Biol Chem 275:24977–24983.

    PubMed  CAS  Google Scholar 

  • Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM (2007) Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 64:343–349.

    PubMed  Google Scholar 

  • Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825–838.

    PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2002) Cyclin-dependent kinase 5 is required for associative learning. J Neurosci 22:3700–3707.

    PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2003) Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5. Neuropharmacology 44:1089–1099.

    PubMed  CAS  Google Scholar 

  • Fischer PM, Gianella-Borradori A (2005) Recent progress in the discovery and development of cyclin-dependent kinase inhibitors. Expert Opin Investig Drugs 14:457–477.

    PubMed  CAS  Google Scholar 

  • Gargini C, Terzibasi E, Mazzoni F, Strettoi E (2007) Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: a morphological and ERG study. J Comp Neurol 500:222–238.

    PubMed  Google Scholar 

  • Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z (2003) Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38:33–46.

    PubMed  CAS  Google Scholar 

  • Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495.

    PubMed  CAS  Google Scholar 

  • Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB (1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20:573–579.

    PubMed  CAS  Google Scholar 

  • Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA (1997) Active site-directed antibodies identify calpain ii as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimers-disease. Brain Res 763:145–158.

    PubMed  CAS  Google Scholar 

  • Hallows JL, Iosif RE, Biasell RD, Vincent I (2006) p35/p25 is not essential for tau and cytoskeletal pathology or neuronal loss in Niemann-Pick type C disease. J Neurosci 26:2738–2744.

    PubMed  CAS  Google Scholar 

  • Hampel H, Burger K, Pruessner JC, Zinkowski R, DeBernardis J, Kerkman D, Leinsinger G, Evans AC, Davies P, Moller HJ, Teipel SJ (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 62:770–773.

    PubMed  Google Scholar 

  • Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, Sjoegren M, DeBernardis J, Kerkman D, Ishiguro K, Ohno H, Vanmechelen E, Vanderstichele H, McCulloch C, Moller HJ, Davies P, Blennow K (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 61:95–102.

    PubMed  CAS  Google Scholar 

  • Han P, Dou F, Li F, Zhang X, Zhang YW, Zheng H, Lipton SA, Xu H, Liao FF (2005) Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of tau phosphorylation. J Neurosci 25:11542–11552.

    PubMed  CAS  Google Scholar 

  • Hardy J (2006) Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal. J Alzheimers Dis 9:151–153.

    PubMed  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356.

    PubMed  CAS  Google Scholar 

  • Hashiguchi M, Saito T, Hisanaga S, Hashiguchi T (2002) Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. J Biol Chem 277:44525–44530.

    PubMed  CAS  Google Scholar 

  • Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10:880–886.

    Google Scholar 

  • Hayashi F, Matsuura I, Kachi S, Maeda T, Yamamoto M, Fujii Y, Liu H, Yamazaki M, Usukura J, Yamazaki A (2000) Phosphorylation by cyclin-dependent protein kinase 5 of the regulatory subunit of retinal cGMP phosphodiesterase. II. Its role in the turnoff of phosphodiesterase in vivo. J Biol Chem 275:32958–32965.

    PubMed  CAS  Google Scholar 

  • Humbert S, Dhavan R, Tsai L (2000) p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci 113(Pt 6):975–983.

    PubMed  CAS  Google Scholar 

  • Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705.

    PubMed  CAS  Google Scholar 

  • Illanes O, Anderson S, Niesman M, Zwick L, Jessen BA (2006) Retinal and peripheral nerve toxicity induced by the administration of a pan-cyclin dependent kinase (cdk) inhibitor in mice. Toxicol Pathol 34:243–248.

    PubMed  CAS  Google Scholar 

  • Ishiguro K, Kobayashi S, Omori A, Takamatsu M, Yonekura S, Anzai K, Imahori K, Uchida T (1994) Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain. FEBS Lett 342:203–208.

    PubMed  CAS  Google Scholar 

  • Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34:509–519.

    PubMed  CAS  Google Scholar 

  • Jamsa A, Backstrom A, Gustafsson E, Dehvari N, Hiller G, Cowburn RF, Vasange M (2006) Glutamate treatment and p25 transfection increase Cdk5 mediated tau phosphorylation in SH-SY5Y cells. Biochem Biophys Res Commun 345:324–331.

    PubMed  Google Scholar 

  • Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 25:8843–8853.

    PubMed  CAS  Google Scholar 

  • Lau KF, Howlett DR, Kesavapany S, Standen CL, Dingwall C, McLoughlin DM, Miller CC (2002) Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability. Mol Cell Neurosci 20:13–20.

    PubMed  CAS  Google Scholar 

  • Le Corre S, Klafki HW, Plesnila N, Hubinger G, Obermeier A, Sahagun H, Monse B, Seneci P, Lewis J, Eriksen J, Zehr C, Yue M, McGowan E, Dickson DW, Hutton M, Roder HM (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci USA 103:9673–9678.

    PubMed  Google Scholar 

  • Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN (1999) Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res 34:21–29.

    PubMed  CAS  Google Scholar 

  • Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, Neve R, Ahlijanian MK, Tsai LH (2003) APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 163:83–95.

    PubMed  CAS  Google Scholar 

  • Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364.

    PubMed  CAS  Google Scholar 

  • Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159.

    PubMed  CAS  Google Scholar 

  • Lefevre K, Clarke PG, Danthe EE, Castagne V (2002) Involvement of cyclin-dependent kinases in axotomy-induced retinal ganglion cell death. J Comp Neurol 447:72–81.

    PubMed  CAS  Google Scholar 

  • Lem J, Flannery JG, Li T, Applebury ML, Farber DB, Simon MI (1992) Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit. Proc Natl Acad Sci USA 89:4422–4426.

    PubMed  CAS  Google Scholar 

  • Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH (1994) A brain-specific activator of cyclin-dependent kinase 5. Nature 371:423–426.

    PubMed  CAS  Google Scholar 

  • Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491.

    PubMed  CAS  Google Scholar 

  • Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405.

    PubMed  CAS  Google Scholar 

  • Li G, Faibushevich A, Turunen BJ, Yoon SO, Georg G, Michaelis ML, Dobrowsky RT (2003) Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons. J Neurochem 84:347–362.

    PubMed  CAS  Google Scholar 

  • Lilja L, Johansson JU, Gromada J, Mandic SA, Fried G, Berggren PO, Bark C (2004) Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J Biol Chem 279:29534–29541.

    PubMed  CAS  Google Scholar 

  • Lilja L, Yang SN, Webb DL, Juntti-Berggren L, Berggren PO, Bark C (2001) Cyclin-dependent kinase 5 promotes insulin exocytosis. J Biol Chem 276:34199–34205.

    PubMed  CAS  Google Scholar 

  • Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2002) Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta. FEBS Lett 530:209–214.

    PubMed  CAS  Google Scholar 

  • Liu F, Su Y, Li B, Zhou Y, Ryder J, Gonzalez-DeWhitt P, May PC, Ni B (2003) Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett 547:193–196.

    PubMed  CAS  Google Scholar 

  • Lund ET, McKenna R, Evans DB, Sharma SK, Mathews WR (2001) Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry. J Neurochem 76:1221–1232.

    PubMed  CAS  Google Scholar 

  • Ma C, Papermaster D, Cepko CL (1998) A unique pattern of photoreceptor degeneration in cyclin D1 mutant mice. Proc Natl Acad Sci USA 95:9938–9943.

    PubMed  CAS  Google Scholar 

  • Maas Jr. JW, Horstmann S, Borasio GD, Anneser JM, Shooter EM, Kahle PJ (1998) Apoptosis of central and peripheral neurons can be prevented with cyclin-dependent kinase/mitogen-activated protein kinase inhibitors. J Neurochem 70:1401–1410.

    PubMed  CAS  Google Scholar 

  • MacPherson D, Sage J, Kim T, Ho D, McLaughlin ME, Jacks T (2004) Cell type-specific effects of Rb deletion in the murine retina. Genes Dev 18:1681–1694.

    PubMed  CAS  Google Scholar 

  • Matsuura I, Bondarenko VA, Maeda T, Kachi S, Yamazaki M, Usukura J, Hayashi F, Yamazaki A (2000) Phosphorylation by cyclin-dependent protein kinase 5 of the regulatory subunit of retinal cGMP phosphodiesterase. I. Identification of the kinase and its role in the turnoff of phosphodiesterase in vitro. J Biol Chem 275:32950–32957.

    PubMed  CAS  Google Scholar 

  • Morioka M, Kawano T, Yano S, Kai Y, Tsuiki H, Yoshinaga Y, Matsumoto J, Maeda T, Hamada J, Yamamoto H, Fukunaga K, Kuratsu J (2006) Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. Biochem Biophys Res Commun 347:273–278.

    PubMed  CAS  Google Scholar 

  • Nath R, Davis M, Probert AW, Kupina NC, Ren X, Schielke GP, Wang KK (2000) Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells. Biochem Biophys Res Commun 274:16–21.

    PubMed  CAS  Google Scholar 

  • Nguyen MD, Lariviere RC, Julien JP (2001) Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron 30:135–147.

    PubMed  CAS  Google Scholar 

  • Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, Davies P, Burns M, Veeranna, Nixon R, Dickson D, Matsuoka Y, Ahlijanian M, Lau LF, Duff K (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565.

    Google Scholar 

  • Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995.

    PubMed  CAS  Google Scholar 

  • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140.

    PubMed  CAS  Google Scholar 

  • Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 24:1063–1070.

    PubMed  CAS  Google Scholar 

  • Ohshima T, Ogura H, Tomizawa K, Hayashi K, Suzuki H, Saito T, Kamei H, Nishi A, Bibb JA, Hisanaga S, Matsui H, Mikoshiba K (2005) Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J Neurochem 94:917–925.

    PubMed  CAS  Google Scholar 

  • Otth C, Concha, II, Arendt T, Stieler J, Schliebs R, Gonzalez-Billault C, Maccioni RB (2002) AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimers Dis 4:417–430.

    PubMed  CAS  Google Scholar 

  • Otth C, Mendoza-Naranjo A, Mujica L, Zambrano A, Concha, II, Maccioni RB (2003) Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease. Neuroreport 14:2403–2409.

    Google Scholar 

  • Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622.

    PubMed  CAS  Google Scholar 

  • Patzke H, Tsai LH (2002) Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. J Biol Chem 277:8054–8060.

    PubMed  CAS  Google Scholar 

  • Paudel HK, Lew J, Ali Z, Wang JH (1993) Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments. J Biol Chem 268:23512–23518.

    PubMed  CAS  Google Scholar 

  • Pei JJ, Grundke-Iqbal I, Iqbal K, Bogdanovic N, Winblad B, Cowburn RF (1998) Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration. Brain Res 797:267–277.

    PubMed  CAS  Google Scholar 

  • Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825.

    PubMed  CAS  Google Scholar 

  • Rademakers R, Sleegers K, Theuns J, Van den Broeck M, Bel Kacem S, Nilsson LG, Adolfsson R, van Duijn CM, Van Broeckhoven C, Cruts M (2005) Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease. Neurobiol Aging 26:1145–1151.

    PubMed  CAS  Google Scholar 

  • Ramiro-Ibanez F, Trajkovic D, Jessen B (2005) Gastric and pancreatic lesions in rats treated with a pan-CDK inhibitor. Toxicol Pathol 33:784–791.

    PubMed  CAS  Google Scholar 

  • Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22:44–52.

    PubMed  CAS  Google Scholar 

  • Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99:6364–6369.

    PubMed  CAS  Google Scholar 

  • Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA (2007) GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers. Neuron 54:713–720.

    PubMed  CAS  Google Scholar 

  • Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316:750–754.

    PubMed  CAS  Google Scholar 

  • Ruben GC, Ciardelli TL, Grundke-Iqbal I, Iqbal K (1997) Alzheimer disease hyperphosphorylated tau aggregates hydrophobically. Synapse 27:208–229.

    PubMed  CAS  Google Scholar 

  • Saito K, Elce JS, Hamos JE, Nixon RA (1993) Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci USA 90:2628–2632.

    PubMed  CAS  Google Scholar 

  • Sakaue F, Saito T, Sato Y, Asada A, Ishiguro K, Hasegawa M, Hisanaga S (2005) Phosphorylation of FTDP-17 mutant tau by cyclin-dependent kinase 5 complexed with p35, p25, or p39. J Biol Chem 280:31522–31529.

    PubMed  CAS  Google Scholar 

  • Sano Y, Nakaya T, Pedrini S, Takeda S, Iijima-Ando K, Iijima K, Mathews PM, Itohara S, Gandy S, Suzuki T (2006) Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP. PLoS ONE 1:e51.

    PubMed  Google Scholar 

  • Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481.

    PubMed  CAS  Google Scholar 

  • Senderowicz AM, Sausville EA (2000) Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92:376–387.

    PubMed  CAS  Google Scholar 

  • Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K (1998) Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357:299–309.

    PubMed  CAS  Google Scholar 

  • Sharma P, Sharma M, Amin ND, Albers RW, Pant HC (1999) Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation. Proc Natl Acad Sci USA 96:11156–11160.

    PubMed  CAS  Google Scholar 

  • Shelton SB, Krishnamurthy P, Johnson GV (2004) Effects of cyclin-dependent kinase-5 activity on apoptosis and tau phosphorylation in immortalized mouse brain cortical cells. J Neurosci Res 76:110–120.

    PubMed  CAS  Google Scholar 

  • Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, O'Hare MJ, Callaghan S, Slack RS, Przedborski S, Anisman H, Park DS (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 100:13650–13655.

    PubMed  CAS  Google Scholar 

  • Smith PD, Mount MP, Shree R, Callaghan S, Slack RS, Anisman H, Vincent I, Wang X, Mao Z, Park DS (2006) Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci 26:440–447.

    PubMed  CAS  Google Scholar 

  • Son M, Lee H, Kim M, Ha I, Chung S (2005) Enhancement of BACE1 activity by p25/cdk5-mediated phosphorylation in Alzheimer's disease. Soc Neurosci Abstr Program # 661.4.

    Google Scholar 

  • Spillantini MG, Goedert M (1998) Tau protein pathology in neurodegenerative diseases. Trends Neurosci 21:428–433.

    PubMed  CAS  Google Scholar 

  • Steinhilb ML, Dias-Santagata D, Mulkearns EE, Shulman JM, Biernat J, Mandelkow EM, Feany MB (2007) S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. J Neurosci Res 85:1271–1278.

    PubMed  CAS  Google Scholar 

  • Sultana R, Butterfield DA (2007) Regional expression of key cell cycle proteins in brain from subjects with amnestic mild cognitive impairment. Neurochem Res 32:655–662.

    PubMed  CAS  Google Scholar 

  • Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, Bergeson J, Manetti GJ, Zimmermann M, Tang B, Bartko JJ, Cohen RM (2003) Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289:2094–2103.

    PubMed  Google Scholar 

  • Swatton JE, Sellers LA, Faull RL, Holland A, Iritani S, Bahn S (2004) Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci 19:2711–2719.

    PubMed  Google Scholar 

  • Takahashi M, Iseki E, Kosaka K (2000) Cdk5 and munc-18/p67 co-localization in early stage neurofibrillary tangles-bearing neurons in Alzheimer type dementia brains. J Neurol Sci 172:63–69.

    PubMed  CAS  Google Scholar 

  • Takahashi S, Saito T, Hisanaga S, Pant HC, Kulkarni AB (2003) Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules. J Biol Chem 278:10506–10515.

    PubMed  CAS  Google Scholar 

  • Takashima A, Murayama M, Yasutake K, Takahashi H, Yokoyama M, Ishiguro K (2001) Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain. Neurosci Lett 306:37–40.

    PubMed  CAS  Google Scholar 

  • Tandon A, Yu H, Wang L, Rogaeva E, Sato C, Chishti MA, Kawarai T, Hasegawa H, Chen F, Davies P, Fraser PE, Westaway D, St George-Hyslop PH (2003) Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. J Neurochem 86:572–581.

    PubMed  CAS  Google Scholar 

  • Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, Hatase O, Wang JH (1995) An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem 270:26897–26903.

    PubMed  CAS  Google Scholar 

  • Taniguchi S, Fujita Y, Hayashi S, Kakita A, Takahashi H, Murayama S, Saido TC, Hisanaga S, Iwatsubo T, Hasegawa M (2001) Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains. FEBS Lett 489:46–50.

    PubMed  CAS  Google Scholar 

  • Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A (2001) Structure and regulation of the CDK5-p25(nck5a) complex. Mol Cell 8:657–669.

    PubMed  CAS  Google Scholar 

  • Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62:1984–1989.

    PubMed  CAS  Google Scholar 

  • Tomidokoro Y, Ishiguro K, Harigaya Y, Matsubara E, Ikeda M, Park JM, Yasutake K, Kawarabayashi T, Okamoto K, Shoji M (2001) Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. Neurosci Lett 299:169–172.

    PubMed  CAS  Google Scholar 

  • Town T, Zolton J, Shaffner R, Schnell B, Crescentini R, Wu Y, Zeng J, DelleDonne A, Obregon D, Tan J, Mullan M (2002) p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J Neurosci Res 69:362–372.

    PubMed  CAS  Google Scholar 

  • Tsai LH, Delalle I, Caviness Jr. VS, Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423.

    PubMed  CAS  Google Scholar 

  • Tsang SH, Gouras P, Yamashita CK, Kjeldbye H, Fisher J, Farber DB, Goff SP (1996) Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase. Science 272:1026–1029.

    PubMed  CAS  Google Scholar 

  • Tseng HC, Zhou Y, Shen Y, Tsai LH (2002) A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains. FEBS Lett 523:58–62.

    PubMed  CAS  Google Scholar 

  • Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 19:7011–7019.

    PubMed  CAS  Google Scholar 

  • Ubeda M, Kemp DM, Habener JF (2004) Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer's disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology 145:3023–3031.

    PubMed  CAS  Google Scholar 

  • Vallazza-Deschamps G, Cia D, Gong J, Jellali A, Duboc A, Forster V, Sahel JA, Tessier LH, Picaud S (2005) Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors. Eur J Neurosci 22:1013–1022.

    PubMed  Google Scholar 

  • Wang J, Liu S, Fu Y, Wang JH, Lu Y (2003) Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 6:1039–1047.

    PubMed  CAS  Google Scholar 

  • Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 24:3370–3378.

    PubMed  CAS  Google Scholar 

  • Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, Yamada Y, Mikoshiba K, Seino Y, Matsui H, Tomizawa K (2005) Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med 11:1104–1108.

    PubMed  CAS  Google Scholar 

  • Wei W, Wang X, Kusiak JW (2002) Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. J Biol Chem 277:17649–17656.

    PubMed  CAS  Google Scholar 

  • Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, Duff K (2008) Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci 28:2624–2632.

    Google Scholar 

  • Wen Y, Yang S, Liu R, Brun-Zinkernagel AM, Koulen P, Simpkins JW (2004) Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer's disease-like tauopathy in female rats. J Biol Chem 279:22684–22692.

    PubMed  CAS  Google Scholar 

  • Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, Simpkins JW (2007) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772:473–483.

    PubMed  CAS  Google Scholar 

  • Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714.

    PubMed  CAS  Google Scholar 

  • Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K (1996) Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol (Berl) 92:232–241.

    CAS  Google Scholar 

  • Yoo BC, Lubec G (2001) p25 protein in neurodegeneration. Nature 411:763–764; discussion 764–765.

    PubMed  Google Scholar 

  • Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351.

    PubMed  CAS  Google Scholar 

  • Zhai S, Senderowicz AM, Sausville EA, Figg WD (2002) Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development. Ann Pharmacother 36:905–911.

    PubMed  CAS  Google Scholar 

  • Zhang J, Krishnamurthy PK, Johnson GV (2002) Cdk5 phosphorylates p53 and regulates its activity. J Neurochem 81:307–313.

    PubMed  CAS  Google Scholar 

  • Zhang M, Li J, Chakrabarty P, Bu B, Vincent I (2004) Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice. Am J Pathol 165:843–853.

    PubMed  CAS  Google Scholar 

  • Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin N, Albers W, Grant P, Pant HC (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. Embo J 24:209–220.

    PubMed  CAS  Google Scholar 

  • Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA, Tsai LH (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26:633–646.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lit-Fui Lau .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Lau, LF., Hicks, C.D. (2008). Cdk5 as a Drug Target for Alzheimer’s Disease. In: Ip, N.Y., Tsai, LH. (eds) Cyclin Dependent Kinase 5 (Cdk5). Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78887-6_18

Download citation