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


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.


Progranulin Alzheimer’s disease Microglia TREM2 C1q Tau 



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 ( 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)


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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

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