Jansen‐West, Karen

A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151

Sortilin 1 regulates the levels of brain progranulin (PGRN), a neurotrophic growth factor that, when deficient, is linked to cases of frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43)–positive inclusions (FTLD-TDP). We identified a specific splicing enhancer element that regulates the inclusion of a sortilin exon cassette (termed Ex17b) not normally present in the mature sortilin mRNA. This enhancer element is consistently present in sortilin RNA of mice and other species but absent in primates, which carry a premature stop codon within the Ex17b sequence. In the absence of TDP-43, which acts as a regulatory inhibitor, Ex17b is included in the sortilin mRNA. In humans, in contrast to mice, the inclusion of Ex17b in sortilin mRNA generates a truncated, nonfunctional, extracellularly released protein that binds to but does not internalize PGRN, essentially acting as a decoy receptor. Based on these results, we propose a potential mechanism linking misregulation of sortilin splicing with altered PGRN metabolism.

Proinflammatory stimuli, after amyloid β (Aβ) deposition, have been hypothesized to create a self‐reinforcing positive feedback loop that increases amyloidogenic processing of the Aβ precursor protein (APP), promoting further Aβ accumulation and neuroinflammation in Alzheimer's disease (AD). Interleukin‐6 (IL‐6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction. To assess the effects of IL‐6 on Aβ deposition and APP processing in vivo ,we overexpressed murine IL‐6 (mIL‐6) in the brains of APP transgenic TgCRND8 and TG2576 mice. mIL‐6 expression resulted in extensive gliosis and concurrently attenuated Aβ deposition in TgCRND8 mouse brains. This was accompanied by up‐regulation of glial phagocytic markers in vivo and resulted in enhanced microglia‐mediated phagocytosis of Aβ aggregates in vitro . Further, mIL‐6‐induced neuroinflammation had no effect on APP processing in TgCRND8 and had no effect on APP processing or steady‐state levels of Aβ in young Tg2576 mice. These results indicate that mIL‐6‐mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Aβ plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology. This is the first study that methodically dissects the contribution of mIL‐6 with regard to its potential role in modulating Aβ deposition in vivo .—Chakrabarty, P., Jansen‐West, K., Beccard, A., Ceballos‐Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., Das, P. Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J . 24, 548–559 (2010). www.fasebj.org