Article

Core features of frontotemporal dementia recapitulated in progranulin knockout mice

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Neurobiology of Disease (Impact Factor: 5.08). 09/2011; 45(1):395-408. DOI: 10.1016/j.nbd.2011.08.029
Source: PubMed

ABSTRACT

Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-aged wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected.

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Available from: Nupur Ghoshal, Jan 28, 2014
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    • "Interestingly, an increased methylation of GRN promoter region was described in cells and brains from FTLD, specifically in patients with bvFTD clinical variant (Banzhaf-Strathmann et al., 2013;Galimberti et al., 2013). Different lines of GRN-knockout mice have been produced showing phenotypes that qualifiy them as useful models of FTD (Kayasuga et al., 2007;Yin et al., 2010;Ghoshal et al., 2012). Specifically,Yin et al. (2010)obtained progranulin-deficient mice characterized by phenotypic alterations that resembles what is typically observed in patients with bvFTD. "
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    • "With regard to the odorants, one was familiar (bedding) and one was novel (coconut). Mice tend to poke more often into odorant-containing versus empty corner holes, but show a robust preference for poking into holes containing the familiar scent of (fresh) bedding used in their home cages over a novel odorant [26], [27]. "
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    • "For our experiments, we used primary hippocampal cultures prepared from Grn−/− mice generated by Kayasuga et al. [27], with the knowledge that these mice display accelerated brain aging due to increased accumulation of lipofuscin, in addition to enhanced gliosis and neurodegeneration when compared to WT mice [29]. These Grn−/− mice also mimic behavior changes similar to FTLD patients, including increased aggression, decreased social interaction and impaired learning and memory [27,30]. Even though our mice display increased ubiquitin staining, they are not positive for TDP-43, the neuropathological hallmark of FTLD with GRN mutations. "
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