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Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R, Li Y, Martens LH, Elia LP, Ward ME, Mucke L, Farese RV Jr, Gan L. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models. Nat Med. 2014 Oct;20(10):1157-64. Epub 2014 Sep 28 PubMed.
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University of Antwerp
With several different in vivo and cell culture approaches, including lentiviral PGRN expression and LysM promoter-driven selective ablation of PGRN from microglia, the authors elegantly showed that progranulin, especially from the microglial compartment, protects against Aβ toxicity and reduces amyloid plaque deposition.
While there is no good promoter available for selective ablation in all monocyte/macrophages lineages—for instance, the LysM promoter utilized in this study is not expressed in CD11c-positive monocytes and macrophages, and Grn transcripts in isolated CD11b+ cells were only reduced by half—the authors managed to show a threefold increase in plaque deposition kinetics accompanied by reduced retention of spatial memory. These data corroborate well with the genetic association of PGRN deficiency with increased risk of late-onset AD. While the underlying mechanism remains unidentified, decreased M1-related phagocytosis by brain microglia likely plays an important role in PGRN haploinsufficiency-related FTLD. However, an enhanced M2-phagocytosis of apoptotic neurons in Caenorhabditis elegans lacking the Grn homologue (Kao et al., 2011) also suggests that progranulin’s role in phagocytotic responses can be contextual—and requires further investigation.
Another point I found interesting was the downregulation of parenchymal progranulin in AD mice before plaque deposition in the absence of any changes in the transcript levels. While the issues of cell-bound progranulin (mostly full-length) and cell-free progranulin (full-length and proteolytic peptides) measured by a mouse ELISA employed in the study have to be sorted out first, if true, this downregulation could be an additional cause of neuronal injury in the prodromal stage of AD—and should be addressed in future studies.
References:
Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV, Kenyon C. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4441-6. PubMed.
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