Abstract
Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
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Acknowledgements
We thank M. Finucane for statistical analyses, J. Lau and W. Weiss for technical advice, B. Miller and L. Mitic for discussions, G. Howard and A. Lucido for editorial review, J. Carroll and T. Roberts for graphics assistance, V. Shen and R. Chen for technical assistance, E.H. Koo (University of California San Diego) and P. Davies (Albert Einstein College of Medicine) for CT-15 and PHF-1 antibodies, respectively, and L. Goss for administrative assistance. This work was supported in part by the Consortium for Frontotemporal Dementia Research (L.G. and R.V.F.), the US National Institutes of Health (1R01AG036884 and R01AG030207 to L.G.) and the Stephen D. Bechtel Jr. Foundation. S.S.M. is supported by US National Institutes of Health fellowship F32NS076239, and L.H.M. is supported by US National Institutes of Health fellowship F31AG034793. Behavioral data were obtained with the help of the Gladstone Institutes' Neurobehavioral Core (supported by US National Institutes of Health grant P30NS065780).
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L.G., S.S.M. and S.-W.M. conceived the project and designed the experiments. S.S.M., S.-W.M., G.K., Y.Z., C.W., Y.L. and R.A. conducted experiments. L.H.M., L.P.E., M.E.W., L.M. and R.V.F. developed experimental tools or mouse models. S.S.M. and L.G. wrote the manuscript.
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Minami, S., Min, SW., Krabbe, G. et al. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20, 1157â1164 (2014). https://doi.org/10.1038/nm.3672
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DOI: https://doi.org/10.1038/nm.3672