التفاصيل البيبلوغرافية
| العنوان: |
Reduction of microglial progranulin does not exacerbate pathology or behavioral deficits in neuronal progranulin-insufficient mice. |
| المؤلفون: |
Arrant, Andrew E.1 (AUTHOR), Filiano, Anthony J.1 (AUTHOR), Patel, Aashka R.1 (AUTHOR), Hoffmann, Madelyn Q.1 (AUTHOR), Boyle, Nicholas R.1 (AUTHOR), Kashyap, Shreya N.1 (AUTHOR), Onyilo, Vincent C.1 (AUTHOR), Young, Allen H.1 (AUTHOR), Roberson, Erik D.1 (AUTHOR) eroberson@uabmc.edu |
| المصدر: |
Neurobiology of Disease. Apr2019, Vol. 124, p152-162. 11p. |
| مصطلحات موضوعية: |
*PROGRANULIN, *FRONTOTEMPORAL lobar degeneration, *NEURONAL ceroid-lipofuscinosis, *FRONTOTEMPORAL dementia, *LYSOSOMAL storage diseases, *PROTEINS |
| مستخلص: |
Abstract Loss-of-function mutations in progranulin (GRN), most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Individuals with loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Progranulin is a secreted glycoprotein expressed by a variety of cell types throughout the body, including neurons and microglia in the brain. Understanding the relative importance of neuronal and microglial progranulin insufficiency in FTD pathogenesis may guide development of therapies. In this study, we used mouse models to investigate the role of neuronal and microglial progranulin insufficiency in the development of FTD-like pathology and behavioral deficits. Grn −/− mice model aspects of FTD and NCL, developing lipofuscinosis and gliosis throughout the brain, as well as deficits in social behavior. We have previously shown that selective depletion of neuronal progranulin disrupts social behavior, but does not produce lipofuscinosis or gliosis. We hypothesized that reduction of microglial progranulin would induce lipofuscinosis and gliosis, and exacerbate behavioral deficits, in neuronal progranulin-deficient mice. To test this hypothesis, we crossed Grn fl/fl mice with mice expressing Cre transgenes targeting neurons (CaMKII -Cre) and myeloid cells/microglia (LysM -Cre). CaMKII -Cre, which is expressed in forebrain excitatory neurons, reduced cortical progranulin protein levels by around 50%. LysM -Cre strongly reduced progranulin immunolabeling in many microglia, but did not reduce total brain progranulin levels, suggesting that, at least under resting conditions, microglia contribute less than neurons to overall brain progranulin levels. Mice with depletion of both neuronal and microglial progranulin failed to develop lipofuscinosis or gliosis, suggesting that progranulin from extracellular sources prevented pathology in cells targeted by the Cre transgenes. Reduction of microglial progranulin also did not exacerbate the social deficits of neuronal progranulin-insufficient mice. These results do not support the hypothesis of synergistic effects between progranulin-deficient neurons and microglia. Nearly complete progranulin deficiency appears to be required to induce lipofuscinosis and gliosis in mice, while partial progranulin insufficiency is sufficient to produce behavioral deficits. Highlights • Depletion of neuronal progranulin reduces cortical progranulin levels by 50%. • Reduction of microglial progranulin using LysM-Cre does not substantially further reduce overall brain progranulin levels. • Reduction of both neuronal and microglial progranulin does not cause lipofuscinosis. • Depletion of neuronal progranulin causes social deficits. • Reduction of microglial progranulin elevates compulsive grooming behavior. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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