title: Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network.
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.
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Klein
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Bhagat
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT, 06536, USA. stephen.strittmatter@yale.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D000077155:Granulins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D000077153:Progranulins; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D058227:Amyloidogenic Proteins; C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D016875:tau Proteins
keywords: Alzheimer’s disease; C1q; Microglia; Progranulin; TREM2; Tau