Advertisement

Acta Neuropathologica

, Volume 133, Issue 5, pp 785–807 | Cite as

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

  • Hideyuki Takahashi
  • Zoe A. Klein
  • Sarah M. Bhagat
  • Adam C. Kaufman
  • Mikhail A. Kostylev
  • Tsuneya Ikezu
  • Stephen M. StrittmatterEmail author
  • For the Alzheimer’s Disease Neuroimaging Initiative
Original Paper

Abstract

Progranulin (PGRN) is implicated in Alzheimer’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer’s disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

Keywords

Progranulin Alzheimer’s disease Microglia TREM2 C1q Tau 

Notes

Acknowledgements

We thank Stefano Sodi and Yiguang Fu for assistance with mouse husbandry. We thank Janghoo Lim for help with the C1000 Thermal Cycler. This work was supported by grants from NIH, BrightFocus Foundation, Alzheimer’s Association and Falk Medical Research Trust to S.M.S. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense Award Number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Compliance with ethical standards

Conflict of interest

S.M.S. is a co-founder of Axerion Therapeutics, seeking to develop NgR- and PrP-based therapeutics.

Supplementary material

401_2017_1668_MOESM1_ESM.pdf (25.5 mb)
Supplementary material 1 (PDF 26091 kb)

References

  1. 1.
    Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J (2010) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 177:311–324. doi: 10.2353/ajpath.2010.090915 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593. doi: 10.1038/nn.4132 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919. doi: 10.1038/nature05016 CrossRefPubMedGoogle Scholar
  4. 4.
    Bhagat SM, Butler SS, Taylor JR, McEwen BS, Strittmatter SM (2016) Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood. Mol Psychiatry 21:1281–1289. doi: 10.1038/mp.2015.179 CrossRefPubMedGoogle Scholar
  5. 5.
    Blank T, Prinz M (2016) CatacLysMic specificity when targeting myeloid cells? Eur J Immunol 46:1340–1342. doi: 10.1002/eji.201646437 CrossRefPubMedGoogle Scholar
  6. 6.
    Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613CrossRefPubMedGoogle Scholar
  7. 7.
    Brouwers N, Nuytemans K, van der Zee J, Gijselinck I, Engelborghs S, Theuns J, Kumar-Singh S, Pickut BA, Pals P, Dermaut B, Bogaerts V, De Pooter T, Serneels S, Van den Broeck M, Cuijt I, Mattheijssens M, Peeters K, Sciot R, Martin JJ, Cras P, Santens P, Vandenberghe R, De Deyn PP, Cruts M, Van Broeckhoven C, Sleegers K (2007) Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 64:1436–1446. doi: 10.1001/archneur.64.10.1436 CrossRefPubMedGoogle Scholar
  8. 8.
    Brouwers N, Sleegers K, Engelborghs S, Maurer-Stroh S, Gijselinck I, van der Zee J, Pickut BA, Van den Broeck M, Mattheijssens M, Peeters K, Schymkowitz J, Rousseau F, Martin JJ, Cruts M, De Deyn PP, Van Broeckhoven C (2008) Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 71:656–664. doi: 10.1212/01.wnl.0000319688.89790.7a CrossRefPubMedGoogle Scholar
  9. 9.
    Buerger K, Alafuzoff I, Ewers M, Pirttila T, Zinkowski R, Hampel H (2007) No correlation between CSF tau protein phosphorylated at threonine 181 with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 130:e82. doi: 10.1093/brain/awm140 CrossRefPubMedGoogle Scholar
  10. 10.
    Buerger K, Ewers M, Pirttila T, Zinkowski R, Alafuzoff I, Teipel SJ, DeBernardis J, Kerkman D, McCulloch C, Soininen H, Hampel H (2006) CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129:3035–3041. doi: 10.1093/brain/awl269 CrossRefPubMedGoogle Scholar
  11. 11.
    Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G (2012) Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 287:32298–32306. doi: 10.1074/jbc.R112.399170 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA (2016) Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci USA 113:10186–10191. doi: 10.1073/pnas.1609896113 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM, Group A-AS (2012) Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 11:669–678. doi: 10.1016/S1474-4422(12)70142-4 CrossRefPubMedGoogle Scholar
  14. 14.
    Colonna M, Wang Y (2016) TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci 17:201–207. doi: 10.1038/nrn.2016.7 CrossRefPubMedGoogle Scholar
  15. 15.
    Condello C, Yuan P, Schain A, Grutzendler J (2015) Microglia constitute a barrier that prevents neurotoxic protofibrillar A beta 42 hotspots around plaques. Nat Commun. doi: 10.1038/Ncomms7176 PubMedPubMedCentralGoogle Scholar
  16. 16.
    Coppola G, Karydas A, Rademakers R, Wang Q, Baker M, Hutton M, Miller BL, Geschwind DH (2008) Gene expression study on peripheral blood identifies progranulin mutations. Ann Neurol 64:92–96. doi: 10.1002/ana.21397 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cortini F, Fenoglio C, Guidi I, Venturelli E, Pomati S, Marcone A, Scalabrini D, Villa C, Clerici F, Dalla Valle E, Mariani C, Cappa S, Bresolin N, Scarpini E, Galimberti D (2008) Novel exon 1 progranulin gene variant in Alzheimer’s disease. Eur J Neurol 15:1111–1117. doi: 10.1111/j.1468-1331.2008.02266.x CrossRefPubMedGoogle Scholar
  18. 18.
    Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT, Skorupa T, Carrell D, Bertelsen S, Bailey M, McKean D, Shulman JM, De Jager PL, Chibnik L, Bennett DA, Arnold SE, Harold D, Sims R, Gerrish A, Williams J, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Peskind ER, Galasko D, Fagan AM, Holtzman DM, Morris JC, GERAD Consortium, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer Disease Genetic Consortium (ADGC), Goate AM (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron 78:256–268. doi: 10.1016/j.neuron.2013.02.026 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. doi: 10.1038/nature05017 CrossRefPubMedGoogle Scholar
  20. 20.
    Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519. doi: 10.1002/ana.20730 CrossRefPubMedGoogle Scholar
  21. 21.
    Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM (2009) Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol Med 1:371–380. doi: 10.1002/emmm.200900048 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fenoglio C, Galimberti D, Cortini F, Kauwe JS, Cruchaga C, Venturelli E, Villa C, Serpente M, Scalabrini D, Mayo K, Piccio LM, Clerici F, Albani D, Mariani C, Forloni G, Bresolin N, Goate AM, Scarpini E (2009) Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer’s disease. J Alzheimers Dis 18:603–612. doi: 10.3233/JAD-2009-1170 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ganz T, Gabayan V, Liao HI, Liu L, Oren A, Graf T, Cole AM (2003) Increased inflammation in lysozyme M-deficient mice in response to Micrococcus luteus and its peptidoglycan. Blood 101:2388–2392. doi: 10.1182/blood-2002-07-2319 CrossRefPubMedGoogle Scholar
  24. 24.
    Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524. doi: 10.1016/j.nbd.2006.08.017 CrossRefPubMedGoogle Scholar
  25. 25.
    Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O’Banion MK (2013) Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 33:5053–5064. doi: 10.1523/JNEUROSCI.4361-12.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Lauren J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367–6374. doi: 10.1523/JNEUROSCI.0395-10.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, van der Zee J, Lang CM, Kremmer E, Martin JJ, Engelborghs S, Kretzschmar HA, Arzberger T, Van Broeckhoven C, Haass C, Capell A (2014) Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127:845–860. doi: 10.1007/s00401-014-1262-6 PubMedGoogle Scholar
  28. 28.
    Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM (2015) Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc Natl Acad Sci USA 112:E3699–E3708. doi: 10.1073/pnas.1510329112 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hafler BP, Klein ZA, Jimmy Zhou Z, Strittmatter SM (2014) Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice. Brain Res 1588:168–174. doi: 10.1016/j.brainres.2014.09.023 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ (2010) Total and phosphorylated tau protein as biological markers of Alzheimer’s disease. Exp Gerontol 45:30–40. doi: 10.1016/j.exger.2009.10.010 CrossRefPubMedGoogle Scholar
  31. 31.
    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. doi: 10.1001/archpsyc.61.1.95 CrossRefPubMedGoogle Scholar
  32. 32.
    Han MR, Schellenberg GD, Wang LS, Alzheimer’s Disease Neuroimaging I (2010) Genome-wide association reveals genetic effects on human Abeta42 and tau protein levels in cerebrospinal fluids: a case control study. BMC Neurol 10:90. doi: 10.1186/1471-2377-10-90 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Heiss JK, Barrett J, Yu Z, Haas LT, Kostylev MA, Strittmatter SM (2016) Early activation of experience-independent dendritic spine turnover in a mouse model of Alzheimer’s disease. Cereb Cortex. doi: 10.1093/cercor/bhw188 PubMedGoogle Scholar
  34. 34.
    Helmfors L, Boman A, Civitelli L, Nath S, Sandin L, Janefjord C, McCann H, Zetterberg H, Blennow K, Halliday G, Brorsson AC, Kagedal K (2015) Protective properties of lysozyme on beta-amyloid pathology: implications for Alzheimer disease. Neurobiol Dis 83:122–133. doi: 10.1016/j.nbd.2015.08.024 CrossRefPubMedGoogle Scholar
  35. 35.
    Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Science Transl Med 3:77sr71. doi: 10.1126/scitranslmed.3002369 Google Scholar
  36. 36.
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li SM, Ramakrishnan S, Merry KM, Shi QQ, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716. doi: 10.1126/science.aad8373 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hosokawa M, Arai T, Masuda-Suzukake M, Kondo H, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H (2015) Progranulin reduction is associated with increased tau phosphorylation in P301L tau transgenic mice. J Neuropathol Exp Neurol 74:158–165. doi: 10.1097/NEN.0000000000000158 CrossRefPubMedGoogle Scholar
  38. 38.
    Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654–667. doi: 10.1016/j.neuron.2010.09.034 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170. doi: 10.1093/hmg/ddh019 CrossRefPubMedGoogle Scholar
  40. 40.
    Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV Jr, Kenyon C (2011) A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci USA 108:4441–4446. doi: 10.1073/pnas.1100650108 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Karch CM, Cruchaga C, Goate AM (2014) Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83:11–26. doi: 10.1016/j.neuron.2014.05.041 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K, Kotaki H, Horai R, Iwakura Y, Nishihara M (2007) Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 185:110–118. doi: 10.1016/j.bbr.2007.07.020 CrossRefPubMedGoogle Scholar
  43. 43.
    Kelley BJ, Haidar W, Boeve BF, Baker M, Shiung M, Knopman DS, Rademakers R, Hutton M, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Petersen RC (2010) Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin. Arch Neurol 67:171–177. doi: 10.1001/archneurol.2010.113 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kepe V, Moghbel MC, Langstrom B, Zaidi H, Vinters HV, Huang SC, Satyamurthy N, Doudet D, Mishani E, Cohen RM, Hoilund-Carlsen PF, Alavi A, Barrio JR (2013) Amyloid-beta positron emission tomography imaging probes: a critical review. J Alzheimers Dis 36:613–631. doi: 10.3233/JAD-130485 PubMedPubMedCentralGoogle Scholar
  45. 45.
    Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM (2009) Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64:632–644. doi: 10.1016/j.neuron.2009.11.013 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kim S, Swaminathan S, Shen L, Risacher SL, Nho K, Foroud T, Shaw LM, Trojanowski JQ, Potkin SG, Huentelman MJ, Craig DW, DeChairo BM, Aisen PS, Petersen RC, Weiner MW, Saykin AJ, Alzheimer’s Disease Neuroimaging I (2011) Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology 76:69–79. doi: 10.1212/WNL.0b013e318204a397 CrossRefPubMedGoogle Scholar
  47. 47.
    Kleinberger G, Capell A, Haass C, Van Broeckhoven C (2013) Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol 47:337–360. doi: 10.1007/s12035-012-8380-8 CrossRefPubMedGoogle Scholar
  48. 48.
    Lant SB, Robinson AC, Thompson JC, Rollinson S, Pickering-Brown S, Snowden JS, Davidson YS, Gerhard A, Mann DM (2014) Patterns of microglial cell activation in frontotemporal lobar degeneration. Neuropathol Appl Neurobiol 40:686–696. doi: 10.1111/nan.12092 CrossRefPubMedGoogle Scholar
  49. 49.
    Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna) 117:949–960. doi: 10.1007/s00702-010-0433-4 CrossRefGoogle Scholar
  50. 50.
    Lee MJ, Chen TF, Cheng TW, Chiu MJ (2011) rs5848 variant of progranulin gene is a risk of Alzheimer’s disease in the Taiwanese population. Neurodegener Dis 8:216–220. doi: 10.1159/000322538 CrossRefPubMedGoogle Scholar
  51. 51.
    Lee S, Xu G, Jay TR, Bhatta S, Kim KW, Jung S, Landreth GE, Ransohoff RM, Lamb BT (2014) Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J Neurosci 34:12538–12546. doi: 10.1523/JNEUROSCI.0853-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Leverenz JB, Yu CE, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee VM, Schellenberg GD, Bird TD (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374. doi: 10.1093/brain/awm069 CrossRefPubMedGoogle Scholar
  53. 53.
    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV Jr, Paz JT, Barres BA, Huang EJ (2016) Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165:921–935. doi: 10.1016/j.cell.2016.04.001 CrossRefPubMedGoogle Scholar
  54. 54.
    Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138:1738–1755. doi: 10.1093/brain/awv081 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ, Farese RV Jr (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest 122:3955–3959. doi: 10.1172/JCI63113 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R, Li Y, Martens LH, Elia LP, Ward ME, Mucke L, Farese RV Jr, Gan L (2014) Progranulin protects against amyloid beta deposition and toxicity in Alzheimer’s disease mouse models. Nat Med 20:1157–1164. doi: 10.1038/nm.3672 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nicholson AM, Finch NA, Thomas CS, Wojtas A, Rutherford NJ, Mielke MM, Roberts RO, Boeve BF, Knopman DS, Petersen RC, Rademakers R (2014) Progranulin protein levels are differently regulated in plasma and CSF. Neurology 82:1871–1878. doi: 10.1212/WNL.0000000000000445 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Pereson S, Wils H, Kleinberger G, McGowan E, Vandewoestyne M, Van Broeck B, Joris G, Cuijt I, Deforce D, Hutton M, Van Broeckhoven C, Kumar-Singh S (2009) Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models. J Pathol 219:173–181. doi: 10.1002/path.2580 CrossRefPubMedGoogle Scholar
  59. 59.
    Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G, Grinberg LT, Geschwind D, Seeley WW, Miller BL, Rosen H, Rabinovici G (2013) Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol 70:774–778. doi: 10.1001/2013.jamaneurol.393 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Petkau TL, Leavitt BR (2014) Progranulin in neurodegenerative disease. Trends Neurosci 37:388–398. doi: 10.1016/j.tins.2014.04.003 CrossRefPubMedGoogle Scholar
  61. 61.
    Petkau TL, Neal SJ, Milnerwood A, Mew A, Hill AM, Orban P, Gregg J, Lu G, Feldman HH, Mackenzie IR, Raymond LA, Leavitt BR (2012) Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis 45:711–722. doi: 10.1016/j.nbd.2011.10.016 CrossRefPubMedGoogle Scholar
  62. 62.
    Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M (2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative. Lancet Neurol 6:857–868. doi: 10.1016/S1474-4422(07)70221-1 CrossRefPubMedGoogle Scholar
  63. 63.
    Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, Lincoln SJ, Finch N, Rutherford NJ, Crook RJ, Josephs KA, Boeve BF, Knopman DS, Petersen RC, Parisi JE, Caselli RJ, Wszolek ZK, Uitti RJ, Feldman H, Hutton ML, Mackenzie IR, Graff-Radford NR, Dickson DW (2008) Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 17:3631–3642. doi: 10.1093/hmg/ddn257 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Ramanan VK, Risacher SL, Nho K, Kim S, Swaminathan S, Shen L, Foroud TM, Hakonarson H, Huentelman MJ, Aisen PS, Petersen RC, Green RC, Jack CR, Koeppe RA, Jagust WJ, Weiner MW, Saykin AJ, Alzheimer’s Disease Neuroimaging I (2014) APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study. Mol Psychiatry 19:351–357. doi: 10.1038/mp.2013.19 CrossRefPubMedGoogle Scholar
  65. 65.
    Rosen EY, Wexler EM, Versano R, Coppola G, Gao F, Winden KD, Oldham MC, Martens LH, Zhou P, Farese RV Jr, Geschwind DH (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71:1030–1042. doi: 10.1016/j.neuron.2011.07.021 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47:719–730. doi: 10.1177/002215549904700601 CrossRefPubMedGoogle Scholar
  67. 67.
    Schraen-Maschke S, Sergeant N, Dhaenens CM, Bombois S, Deramecourt V, Caillet-Boudin ML, Pasquier F, Maurage CA, Sablonniere B, Vanmechelen E, Buee L (2008) Tau as a biomarker of neurodegenerative diseases. Biomark Med 2:363–384. doi: 10.2217/17520363.2.4.363 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Schwab C, Klegeris A, McGeer PL (2010) Inflammation in transgenic mouse models of neurodegenerative disorders. Biochim Biophys Acta 1802:889–902. doi: 10.1016/j.bbadis.2009.10.013 CrossRefPubMedGoogle Scholar
  69. 69.
    Shankar GM, Welzel AT, McDonald JM, Selkoe DJ, Walsh DM (2011) Isolation of low-n amyloid beta-protein oligomers from cultured cells, CSF, and brain. Methods Mol Biol 670:33–44. doi: 10.1007/978-1-60761-744-0_3 CrossRefPubMedGoogle Scholar
  70. 70.
    Sheng J, Su L, Xu Z, Chen G (2014) Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer’s disease. Gene 542:141–145. doi: 10.1016/j.gene.2014.03.041 CrossRefPubMedGoogle Scholar
  71. 71.
    Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF (2012) Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 90:1102–1107. doi: 10.1016/j.ajhg.2012.04.021 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA (2013) A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci 33:13460–13474. doi: 10.1523/JNEUROSCI.1333-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Strozyk D, Blennow K, White LR, Launer LJ (2003) CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60:652–656CrossRefPubMedGoogle Scholar
  74. 74.
    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. doi: 10.1001/jama.289.16.2094 CrossRefPubMedGoogle Scholar
  75. 75.
    Tanaka Y, Chambers JK, Matsuwaki T, Yamanouchi K, Nishihara M (2014) Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Acta Neuropathol Commun 2:78. doi: 10.1186/s40478-014-0078-x CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 31:258–261CrossRefGoogle Scholar
  77. 77.
    Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M (2016) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213:667–675. doi: 10.1084/jem.20151948 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LH, Seeley WW, Yu G, Herz J, Filiano AJ, Arrant AE, Roberson ED, Kraft TW, Farese RV Jr, Green A, Gan L (2014) Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med 211:1937–1945. doi: 10.1084/jem.20140214 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Wieghofer P, Knobeloch KP, Prinz M (2015) Genetic targeting of microglia. Glia 63:1–22. doi: 10.1002/glia.22727 CrossRefPubMedGoogle Scholar
  80. 80.
    Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C, Van Broeckhoven C, Kumar-Singh S (2012) Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 228:67–76. doi: 10.1002/path.4043 PubMedGoogle Scholar
  81. 81.
    Xu HM, Tan L, Wan Y, Tan MS, Zhang W, Zheng ZJ, Kong LL, Wang ZX, Jiang T, Tan L, Yu JT (2016) PGRN is associated with late-onset alzheimer’s disease: a case–control replication study and meta-analysis. Mol Neurobiol. doi: 10.1007/s12035-016-9698-4 PubMedCentralGoogle Scholar
  82. 82.
    Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117–128. doi: 10.1084/jem.20091568 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J (2016) TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90:724–739. doi: 10.1016/j.neuron.2016.05.003 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Hideyuki Takahashi
    • 1
  • Zoe A. Klein
    • 1
  • Sarah M. Bhagat
    • 1
  • Adam C. Kaufman
    • 1
  • Mikhail A. Kostylev
    • 1
  • Tsuneya Ikezu
    • 2
  • Stephen M. Strittmatter
    • 1
    Email author
  • For the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and NeurobiologyYale University School of MedicineNew HavenUSA
  2. 2.Department of Pharmacology and Experimental TherapeuticsBoston University School of MedicineBostonUSA

Personalised recommendations