Skip to main content

Advertisement

SpringerLink
Log in

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid β (Aβ) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. Aβ is the proteolytic product from its precursor amyloid precursor protein (APP) by β- and γ- secretase. An optional cleavage by α-secretase happens inside the Aβ domain. ADAM17 is supposed to be the regulated α-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP α fragment and reduction of Aβ generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adlerz L, Holback S, Multhaup G, Iverfeldt K (2007) IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways. J Biol Chem 282(14):10203–10209

    Article  CAS  PubMed  Google Scholar 

  • Aisen PS, Pasinetti GM (1998) Glucocorticoids in Alzheimer’s disease. The story so far. Drugs Aging 12(1):1–6

    Article  CAS  PubMed  Google Scholar 

  • Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alfa Cisse M, Sunyach C, Slack BE, Fisher A, Vincent B, Checler F (2007) M1 and M3 muscarinic receptors control physiological processing of cellular prion by modulating ADAM17 phosphorylation and activity. J Neurosci 27(15):4083–4092

    Article  PubMed  CAS  Google Scholar 

  • Althoff K, Reddy P, Voltz N, Rose-John S, Mullberg J (2000) Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins. Eur J Biochem 267(9):2624–2631

    Article  CAS  PubMed  Google Scholar 

  • Anderson JP, Esch FS, Keim PS, Sambamurti K, Lieberburg I, Robakis NK (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci Lett 128(1):126–128

    Article  CAS  PubMed  Google Scholar 

  • Annaert W, De Strooper B (1999) Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci 22(10):439–443

    Article  CAS  PubMed  Google Scholar 

  • Ard MD, Cole GM, Wei J, Mehrle AP, Fratkin JD (1996) Scavenging of Alzheimer’s amyloid beta-protein by microglia in culture. J Neurosci Res 43(2):190–202

    Article  CAS  PubMed  Google Scholar 

  • Arribas J, Esselens C (2009) ADAM17 as a therapeutic target in multiple diseases. Curr Pharm Des 15(20):2319–2335

    Article  CAS  PubMed  Google Scholar 

  • Bandyopadhyay S, Hartley DM, Cahill CM, Lahiri DK, Chattopadhyay N, Rogers JT (2006) Interleukin-1alpha stimulates non-amyloidogenic pathway by alpha-secretase (ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase. J Neurosci Res 84(1):106–118

    Article  CAS  PubMed  Google Scholar 

  • Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M (1991) Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett 285(1):111–114

    Article  CAS  PubMed  Google Scholar 

  • Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, Brunden KR (1999) Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging 20(6):581–589

    Article  CAS  PubMed  Google Scholar 

  • Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385(6618):729–733

    Article  CAS  PubMed  Google Scholar 

  • Blacker M, Noe MC, Carty TJ, Goodyer CG, LeBlanc AC (2002) Effect of tumor necrosis factor-alpha converting enzyme (TACE) and metalloprotease inhibitor on amyloid precursor protein metabolism in human neurons. J Neurochem 83(6):1349–1357

    Article  CAS  PubMed  Google Scholar 

  • Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B (1999) TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J 13(1):63–68

    CAS  PubMed  Google Scholar 

  • Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6(1):32–43

    Article  CAS  PubMed  Google Scholar 

  • Borroto A, Ruiz-Paz S, de la Torre TV, Borrell-Pages M, Merlos-Suarez A, Pandiella A, Blobel CP, Baselga J, Arribas J (2003) Impaired trafficking and activation of tumor necrosis factor-alpha-converting enzyme in cell mutants defective in protein ectodomain shedding. J Biol Chem 278(28):25933–25939

    Article  CAS  PubMed  Google Scholar 

  • Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, Giubilei F, Gianni W, Trequattrini A, Moro ML, Bernardini S, Caltagirone C, Spalletta G (2008) Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav Immun 22(4):487–492

    Article  CAS  PubMed  Google Scholar 

  • Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27(3):325–355

    Article  CAS  PubMed  Google Scholar 

  • Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130

    Article  CAS  PubMed  Google Scholar 

  • Buxbaum JD, Koo EH, Greengard P (1993) Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc Natl Acad Sci USA 90(19):9195–9198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273(43):27765–27767

    Article  CAS  PubMed  Google Scholar 

  • Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49(5):671–682

    Article  CAS  PubMed  Google Scholar 

  • Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB (2001) In-vivo measurement of activated microglia in dementia. Lancet 358(9280):461–467

    Article  CAS  PubMed  Google Scholar 

  • Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4(3):233–234

    Article  CAS  PubMed  Google Scholar 

  • Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P (1992) Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc Natl Acad Sci USA 89(7):3055–3059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 104(50):19796–19801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho HW, Kim JH, Choi S, Kim HJ (2006) Phospholipase A2 is involved in muscarinic receptor-mediated sAPPalpha release independently of cyclooxygenase or lypoxygenase activity in SH-SY5Y cells. Neurosci Lett 397(3):214–218

    Article  CAS  PubMed  Google Scholar 

  • Cisse M, Braun U, Leitges M, Fisher A, Pages G, Checler F, Vincent B (2011) ERK1-independent alpha-secretase cut of beta-amyloid precursor protein via M1 muscarinic receptors and PKCalpha/epsilon. Mol Cell Neurosci 47(3):223–232

    Article  CAS  PubMed  Google Scholar 

  • Colombo A, Wang H, Kuhn PH, Page R, Kremmer E, Dempsey PJ, Crawford HC, Lichtenthaler SF (2013) Constitutive alpha- and beta-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines. Neurobiol Dis 49:137–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colon AL, Menchen LA, Hurtado O, De Cristobal J, Lizasoain I, Leza JC, Lorenzo P, Moro MA (2001) Implication of TNF-alpha convertase (TACE/ADAM17) in inducible nitric oxide synthase expression and inflammation in an experimental model of colitis. Cytokine 16(6):220–226

    Article  CAS  PubMed  Google Scholar 

  • Correa JD, Starling D, Teixeira AL, Caramelli P, Silva TA (2011) Chemokines in CSF of Alzheimer’s disease patients. Arq Neuropsiquiatr 69(3):455–459

    Article  PubMed  Google Scholar 

  • Cui YH, LeY Zhang X, Gong W, Abe K, Sun R, Van Damme J, Proost P, Wang JM (2002) Up-regulation of FPR2, a chemotactic receptor for amyloid beta 1-42 (A beta 42), in murine microglial cells by TNF alpha. Neurobiol Dis 10(3):366–377

    Article  CAS  PubMed  Google Scholar 

  • Dash PK, Moore AN (1995) Enhanced processing of APP induced by IL-1 beta can be reduced by indomethacin and nordihydroguaiaretic acid. Biochem Biophys Res Commun 208(2):542–548

    Article  CAS  PubMed  Google Scholar 

  • Davis AA, Fritz JJ, Wess J, Lah JJ, Levey AI (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci 30(12):4190–4196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis-Salinas J, Saporito-Irwin SM, Donovan FM, Cunningham DD, Van Nostrand WE (1994) Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor. J Biol Chem 269(36):22623–22627

    CAS  PubMed  Google Scholar 

  • Diaz-Rodriguez E, Montero JC, Esparis-Ogando A, Yuste L, Pandiella A (2002) Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell 13(6):2031–2044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Endres K, Anders A, Kojro E, Gilbert S, Fahrenholz F, Postina R (2003) Tumor necrosis factor-alpha converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation. Eur J Biochem 270(11):2386–2393

    Article  CAS  PubMed  Google Scholar 

  • Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 112(3):440–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248(4959):1122–1124

    Article  CAS  PubMed  Google Scholar 

  • Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC (2012) Intracellular Abeta-oligomers and early inflammation in a model of Alzheimer’s disease. Neurobiol Aging 33(7):1329–1342

    Article  CAS  PubMed  Google Scholar 

  • Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G (1991) Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett 129(2):318–320

    Article  CAS  PubMed  Google Scholar 

  • Fisher A (2008) M1 muscarinic agonists target major hallmarks of Alzheimer’s disease—the pivotal role of brain M1 receptors. Neurodegener Dis 5(3–4):237–240

    Article  CAS  PubMed  Google Scholar 

  • Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, Raines EW (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 276(41):37993–38001

    CAS  PubMed  Google Scholar 

  • Ge YW, Lahiri DK (2002) Regulation of promoter activity of the APP gene by cytokines and growth factors: implications in Alzheimer’s disease. Ann N Y Acad Sci 973:463–467

    Article  CAS  PubMed  Google Scholar 

  • Gendron TF, Petrucelli L (2009) The role of tau in neurodegeneration. Mol Neurodegener 4:13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gitter BD, Boggs LN, May PC, Czilli DL, Carlson CD (2000) Regulation of cytokine secretion and amyloid precursor protein processing by proinflammatory amyloid beta (A beta). Ann N Y Acad Sci 917:154–164

    Article  CAS  PubMed  Google Scholar 

  • Goodwin JL, Uemura E, Cunnick JE (1995) Microglial release of nitric oxide by the synergistic action of beta-amyloid and IFN-gamma. Brain Res 692(1–2):207–214

    Article  CAS  PubMed  Google Scholar 

  • Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86(19):7611–7615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE (1998) Glial-neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 8(1):65–72

    Article  CAS  PubMed  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005a) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O’Banion K, Klockgether T, Van Leuven F, Landreth GE (2005b) Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128(Pt 6):1442–1453

    Article  PubMed  Google Scholar 

  • Hoey SE, Williams RJ, Perkinton MS (2009) Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci 29(14):4442–4460

    Article  CAS  PubMed  Google Scholar 

  • Hooper NM, Turner AJ (2002) The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease. Curr Med Chem 9(11):1107–1119

    Article  CAS  PubMed  Google Scholar 

  • Hotoda N, Koike H, Sasagawa N, Ishiura S (2002) A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem Biophys Res Commun 293(2):800–805

    Article  CAS  PubMed  Google Scholar 

  • Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem 268(31):22959–22962

    CAS  PubMed  Google Scholar 

  • In’t Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345(21):1515–1521

    Article  Google Scholar 

  • Ishizuka K, Kimura T, Igata-yi R, Katsuragi S, Takamatsu J, Miyakawa T (1997) Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin Neurosci 51(3):135–138

    Article  CAS  PubMed  Google Scholar 

  • Jacobsen KT, Adlerz L, Multhaup G, Iverfeldt K (2010) Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-beta precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. J Biol Chem 285(14):10223–10231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalus I, Bormann U, Mzoughi M, Schachner M, Kleene R (2006) Proteolytic cleavage of the neural cell adhesion molecule by ADAM17/TACE is involved in neurite outgrowth. J Neurochem 98(1):78–88

    Article  CAS  PubMed  Google Scholar 

  • Karkkainen I, Rybnikova E, Pelto-Huikko M, Huovila AP (2000) Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. Mol Cell Neurosci 15(6):547–560

    Article  CAS  PubMed  Google Scholar 

  • Killock DJ, Ivetic A (2010) The cytoplasmic domains of TNFalpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem J 428(2):293–304

    Article  CAS  PubMed  Google Scholar 

  • Kim ML, Zhang B, Mills IP, Milla ME, Brunden KR, Lee VM (2008) Effects of TNFalpha-converting enzyme inhibition on amyloid beta production and APP processing in vitro and in vivo. J Neurosci 28(46):12052–12061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE (2009) Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet 18(20):3987–3996

    Article  CAS  PubMed  PubMed Central  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(39):8843–8853

    Article  CAS  PubMed  Google Scholar 

  • Koike H, Tomioka S, Sorimachi H, Saido TC, Maruyama K, Okuyama A, Fujisawa-Sehara A, Ohno S, Suzuki K, Ishiura S (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem J 343(Pt 2):371–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, Fahrenholz F (2006) The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J 20(3):512–514

    CAS  PubMed  Google Scholar 

  • Kong Q, Peterson TS, Baker O, Stanley E, Camden J, Seye CI, Erb L, Simonyi A, Wood WG, Sun GY, Weisman GA (2009) Interleukin-1beta enhances nucleotide-induced and alpha-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y(2) receptor. J Neurochem 109(5):1300–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF (2010) ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29(17):3020–3032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • La Marca R, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A, Salzer JL, Taveggia C (2011) TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14(7):857–865

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA 96(7):3922–3927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Gall SM, Maretzky T, Issuree PD, Niu XD, Reiss K, Saftig P, Khokha R, Lundell D, Blobel CP (2010) ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site. J Cell Sci 123(Pt 22):3913–3922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee RK, Wurtman RJ, Cox AJ, Nitsch RM (1995) Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci USA 92(17):8083–8087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee DC, Sunnarborg SW, Hinkle CL, Myers TJ, Stevenson MY, Russell WE, Castner BJ, Gerhart MJ, Paxton RJ, Black RA, Chang A, Jackson LF (2003) TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann N Y Acad Sci 995:22–38

    Article  CAS  PubMed  Google Scholar 

  • Lee EJ, Han JE, Woo MS, Shin JA, Park EM, Kang JL, Moon PG, Baek MC, Son WS, Ko YT, Choi JW, Kim HS (2014) Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-alpha activation. J Immunol 193(5):2384–2393

    Article  CAS  PubMed  Google Scholar 

  • Li X, Maretzky T, Weskamp G, Monette S, Qing X, Issuree PD, Crawford HC, McIlwain DR, Mak TW, Salmon JE, Blobel CP (2015) iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling. Proc Natl Acad Sci USA 112(19):6080–6085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20(15):5709–5714

    CAS  PubMed  Google Scholar 

  • Liu G, Jiang Y, Wang P, Feng R, Jiang N, Chen X, Song H, Chen Z (2012) Cell adhesion molecules contribute to Alzheimer’s disease: multiple pathway analyses of two genome-wide association studies. J Neurochem 120(1):190–198

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Perez E, Zhang Y, Frank SJ, Creemers J, Seidah N, Checler F (2001) Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J Neurochem 76(5):1532–1539

    Article  CAS  PubMed  Google Scholar 

  • Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J (2001) Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia 35(1):72–79

    Article  CAS  PubMed  Google Scholar 

  • Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232

    Article  CAS  PubMed  Google Scholar 

  • Ma G, Chen S, Wang X, Ba M, Yang H, Lu G (2005) Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-secretase cleavage in neuroglioma U251 cells. J Neurosci Res 80(5):683–692

    Article  CAS  PubMed  Google Scholar 

  • Malaguarnera L, Motta M, Di Rosa M, Anzaldi M, Malaguarnera M (2006) Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer’s disease and vascular dementia. Neuropathology 26(4):307–312

    Article  PubMed  Google Scholar 

  • Manthey D, Heck S, Engert S, Behl C (2001) Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway. Eur J Biochem 268(15):4285–4291

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47(2):425–432

    Article  CAS  PubMed  Google Scholar 

  • Merlos-Suarez A, Fernandez-Larrea J, Reddy P, Baselga J, Arribas J (1998) Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J Biol Chem 273(38):24955–24962

    Article  CAS  PubMed  Google Scholar 

  • Merlos-Suarez A, Ruiz-Paz S, Baselga J, Arribas J (2001) Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. J Biol Chem 276(51):48510–48517

    CAS  PubMed  Google Scholar 

  • Milla ME, Leesnitzer MA, Moss ML, Clay WC, Carter HL, Miller AB, Su JL, Lambert MH, Willard DH, Sheeley DM, Kost TA, Burkhart W, Moyer M, Blackburn RK, Pahel GL, Mitchell JL, Hoffman CR, Becherer JD (1999) Specific sequence elements are required for the expression of functional tumor necrosis factor-alpha-converting enzyme (TACE). J Biol Chem 274(43):30563–30570

    Article  CAS  PubMed  Google Scholar 

  • Mishra HK, Long C, Bahaie NS, Walcheck B (2015) Regulation of CXCR2 expression and function by a disintegrin and metalloprotease-17 (ADAM17). J Leukoc Biol 97(3):447–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16(5):631–648

    Article  CAS  PubMed  Google Scholar 

  • Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Warner J, Willard D, Becherer JD (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385(6618):733–736

    Article  CAS  PubMed  Google Scholar 

  • Neher JJ, Neniskyte U, Brown GC (2012) Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front Pharmacol 3:27

    Article  PubMed  PubMed Central  Google Scholar 

  • Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258(5080):304–307

    Article  CAS  PubMed  Google Scholar 

  • Nitsch RM, Kim C, Growdon JH (1998) Vasopressin and bradykinin regulate secretory processing of the amyloid protein precursor of Alzheimer’s disease. Neurochem Res 23(5):807–814

    Article  CAS  PubMed  Google Scholar 

  • Okamoto I, Kawano Y, Murakami D, Sasayama T, Araki N, Miki T, Wong AJ, Saya H (2001) Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J Cell Biol 155(5):755–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozturk C, Ozge A, Yalin OO, Yilmaz IA, Delialioglu N, Yildiz C, B Tesdelen, Kudiaki C (2007) The diagnostic role of serum inflammatory and soluble proteins on dementia subtypes: correlation with cognitive and functional decline. Behav Neurol 18(4):207–215

    Article  PubMed  Google Scholar 

  • Paresce DM, Chung H, Maxfield FR (1997) Slow degradation of aggregates of the Alzheimer’s disease amyloid beta-protein by microglial cells. J Biol Chem 272(46):29390–29397

    Article  CAS  PubMed  Google Scholar 

  • Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ (2005) Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation 2(1):9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA (1998) An essential role for ectodomain shedding in mammalian development. Science 282(5392):1281–1284

    Article  CAS  PubMed  Google Scholar 

  • Postina R (2012) Activation of alpha-secretase cleavage. J Neurochem 120(Suppl 1):46–54

    Article  CAS  PubMed  Google Scholar 

  • Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113(10):1456–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian M, Bai SA, Brogdon B, Wu JT, Liu RQ, Covington MB, Vaddi K, Newton RC, Fossler MJ, Garner CE, Deng Y, Maduskuie T, Trzaskos J, Duan JJ, Decicco CP, Christ DD (2007) Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme in rodents, dogs, chimpanzees, and humans. Drug Metab Dispos 35(10):1916–1925

    Article  CAS  PubMed  Google Scholar 

  • Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero D, Perez B, Clos MV, Badia A (2013) Huprine X and huperzine A improve cognition and regulate some neurochemical processes related with Alzheimer’s disease in triple transgenic mice (3xTg-AD). Neurodegener Dis 11(3):129–140

    Article  CAS  PubMed  Google Scholar 

  • Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA (2000) Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275(19):14608–14614

    Article  CAS  PubMed  Google Scholar 

  • Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J 24(4):742–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saftig P, Reiss K (2011) The “A Disintegrin And Metalloproteases” ADAM10 and ADAM17: novel drug targets with therapeutic potential? Eur J Cell Biol 90(6–7):527–535

    Article  CAS  PubMed  Google Scholar 

  • Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164(5):769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santiago-Josefat B, Esselens C, Bech-Serra JJ, Arribas J (2007) Post-transcriptional up-regulation of ADAM17 upon epidermal growth factor receptor activation and in breast tumors. J Biol Chem 282(11):8325–8331

    Article  CAS  PubMed  Google Scholar 

  • Sastre M, Walter J, Gentleman SM (2008) Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 5:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173–177

    Article  CAS  PubMed  Google Scholar 

  • Seals DF, Courtneidge SA (2003) The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 17(1):7–30

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 8(11):447–453

    Article  CAS  PubMed  Google Scholar 

  • Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Kennedy JP, Jadhav SB, Menon UN, Xiang Z, Watson ML, Christian EP, Doherty JJ, Quirk MC, Snyder DH, Lah JJ, Levey AI, Nicolle MM, Lindsley CW, Conn PJ (2009) A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. J Neurosci 29(45):14271–14286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM (2000) Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J Biol Chem 275(4):2568–2575

    Article  CAS  PubMed  Google Scholar 

  • Skovronsky DM, Fath S, Lee VM, Milla ME (2001) Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. J Neurobiol 49(1):40–46

    Article  CAS  PubMed  Google Scholar 

  • Slack BE, Breu J, Muchnicki L, Wurtman RJ (1997) Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. Biochem J 327(Pt 1):245–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slack BE, Ma LK, Seah CC (2001) Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme. Biochem J 357(Pt 3):787–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M (2000) Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J 14(7):1015–1022

    CAS  PubMed  Google Scholar 

  • Solomon KA, Pesti N, Wu G, Newton RC (1999) Cutting edge: a dominant negative form of TNF-alpha converting enzyme inhibits proTNF and TNFRII secretion. J Immunol 163(8):4105–4108

    CAS  PubMed  Google Scholar 

  • Soond SM, Everson B, Riches DW, Murphy G (2005) ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci 118(Pt 11):2371–2380

    Article  CAS  PubMed  Google Scholar 

  • Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8(6):429–431

    Article  PubMed  Google Scholar 

  • Stoeck A, Keller S, Riedle S, Sanderson MP, Runz S, Le Naour F, Gutwein P, Ludwig A, Rubinstein E, Altevogt P (2006) A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem J 393(Pt 3):609–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B (1992) Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Lab Invest 66(2):223–230

    CAS  PubMed  Google Scholar 

  • Sun Q, Hampel H, Blennow K, Lista S, Levey A, Tang B, Li R, Shen Y (2014) Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer’s disease. J Alzheimers Dis 41(3):877–886

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sunnarborg SW, Hinkle CL, Stevenson M, Russell WE, Raska CS, Peschon JJ, Castner BJ, Gerhart MJ, Paxton RJ, Black RA, Lee DC (2002) Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 277(15):12838–12845

    Article  CAS  PubMed  Google Scholar 

  • Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, Murayama S, Endo T, Sakaguchi G, Kato A, Kitazume S, Hashimoto Y (2008) Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem 104(5):1387–1393

    Article  CAS  PubMed  Google Scholar 

  • Town T, Nikolic V, Tan J (2005) The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflammation 2:24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741

    Article  CAS  PubMed  Google Scholar 

  • Vingtdeux V, Marambaud P (2012) Identification and biology of alpha-secretase. J Neurochem 120(Suppl 1):34–45

    Article  CAS  PubMed  Google Scholar 

  • Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18(12):1812–1819

    Article  CAS  PubMed  Google Scholar 

  • Wang R, Meschia JF, Cotter RJ, Sisodia SS (1991) Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J Biol Chem 266(25):16960–16964

    CAS  PubMed  Google Scholar 

  • Wei Z, Yu D, Bi Y, Cao Y (2015) A disintegrin and metalloprotease 17 promotes microglial cell survival via epidermal growth factor receptor signalling following spinal cord injury. Mol Med Rep 12(1):63–70

    CAS  PubMed  PubMed Central  Google Scholar 

  • Welt T, Kulic L, Hoey SE, McAfoose J, Späni C, Chadha AS, Fisher A, Nitsch RM (2015) Acute effects of muscarinic M1 receptor modulation on AβPP metabolism and amyloid-β levels in vivo: a microdialysis study. J Alzheimers Dis. doi:10.3233/JAD-150152

    PubMed  Google Scholar 

  • Weskamp G, Cai H, Brodie TA, Higashyama S, Manova K, Ludwig T, Blobel CP (2002) Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Mol Cell Biol 22(5):1537–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiley JC, Pettan-Brewer C, Ladiges WC (2011) Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell 10(3):418–428

    Article  CAS  PubMed  Google Scholar 

  • Xia MQ, Hyman BT (1999) Chemokines/chemokine receptors in the central nervous system and Alzheimer’s disease. J Neurovirol 5(1):32–41

    Article  CAS  PubMed  Google Scholar 

  • Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT (1998) Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol 153(1):31–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci 23(20):7504–7509

    CAS  PubMed  Google Scholar 

  • Yu W, Wang H, Ying H, Yu Y, Chen D, Ge W, Shi L (2014) Daphnetin attenuates microglial activation and proinflammatory factor production via multiple signaling pathways. Int Immunopharmacol 21(1):1–9

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Huang Y, Zhu YC, Yao T (2005) Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway. Acta Pharmacol Sin 26(2):171–176

    Article  PubMed  Google Scholar 

  • Zhang H, Ma Q, Zhang YW, Xu H (2012) Proteolytic processing of Alzheimer’s beta-amyloid precursor protein. J Neurochem 120(Suppl 1):9–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu G, Wang D, Lin YH, McMahon T, Koo EH, Messing RO (2001) Protein kinase C epsilon suppresses Abeta production and promotes activation of alpha-secretase. Biochem Biophys Res Commun 285(4):997–1006

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This study was funded by Zhejiang Provincial Natural Science Foundation of China (LQ13C090006).

Author information

Authors and Affiliations

  1. Key Lab of Inflammation and Immunoregulation, School of Medicine, Hangzhou Normal University, Xuelin Street 16, Hangzhou, 310036, China

    Meng Qian, Xiaoqiang Shen & Huanhuan Wang

Authors
  1. Meng Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoqiang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huanhuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huanhuan Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qian, M., Shen, X. & Wang, H. The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease. Cell Mol Neurobiol 36, 471–482 (2016). https://doi.org/10.1007/s10571-015-0232-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-015-0232-4

Keywords

Search

Navigation