title: Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models.
abstract: Amyloid-beta (Abeta) plaques are pathological hallmarks of Alzheimer disease (AD). In addition, innate inflammatory responses, such as those mediated by microglia, are integral to the pathogenesis of AD. Interestingly, only dense-core plaques and not diffuse plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in the brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Abeta-mediated neuropathology, we performed a gene expression analysis on laser-microdissected brain tissue of Tg2576 and APPPS1 mice that are characterized by different types of amyloid plaques and genetic backgrounds. Data were validated by image and biochemical analyses on different ages of Tg2576, APPPS1, and Abeta42-depositing BRI-Abeta42 mice. Consistent with an important role of inflammatory responses in AD, we identified progranulin (mouse Grn; human GRN) as one of the top ten up-regulated molecules in Tg2576 ( approximately 8-fold increased) and APPPS1 ( approximately 2-fold increased) mice compared to littermate controls, and among the eight significantly up-regulated molecules common to both mouse models. In addition, Grn levels correlated significantly with amyloid load, especially the dense-core plaque pathology (p < 0.001). We further showed that Grn is up-regulated in microglia and neurons and neurites around dense-core plaques, but not in astrocytes or oligodendrocytes, as has been shown in AD patients. Our data therefore support the ongoing use of these mouse models in drug trials, especially those with anti-inflammatory compounds. Moreover, the correlation of Grn with increasing disease severity in AD mouse models prompts human studies exploring the viability of GRN as a disease biomarker. Because loss of GRN has recently been shown to cause frontotemporal dementia and serves as a risk factor for AD, the strong GRN reactivity around dense-core plaques is consistent with an important role of this factor in AD pathogenesis.
authors: Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors: Sandra
authors: S
authors: Pereson
authors: Hans
authors: H
authors: Wils
authors: Gernot
authors: G
authors: Kleinberger
authors: Eileen
authors: E
authors: McGowan
authors: Mado
authors: M
authors: Vandewoestyne
authors: Bianca
authors: B
authors: Van Broeck
authors: Geert
authors: G
authors: Joris
authors: Ivy
authors: I
authors: Cuijt
authors: Dieter
authors: D
authors: Deforce
authors: Michael
authors: M
authors: Hutton
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Samir
authors: S
authors: Kumar-Singh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D000077153:Progranulins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins