ABCA1 promotes cholesterol efflux from cells and is required for maintaining plasma cholesterol levels. Cholesterol homeostasis is important in the production of b-amyloid (Ab), a peptide that is overproduced in Alzheimer's disease (AD). Overexpression of ABCA1 can be achieved by stimulating Liver X Receptors (LXR), and changes in Ab have been reported after LXR stimulation in vitro. To determine whether ABCA1 could alter endogenous Ab levels, we used two different in vivo systems. We first examined the effects of an LXR agonist (TO-901317) on wild-type mice and found an increase in brain ABCA1 and apoE levels, which caused an increase in plasma cholesterol. This was accompanied by a decrease in brain Ab levels. We then examined endogenous Ab levels in ABCA1 knockout mice and found that, despite having no ABCA1, lowered brain apoE levels, and lowered plasma cholesterol, there was no change in Ab levels. To assess these in vivo models in an in vitro system, we designed a model in which cholesterol transport via ABCA1 (or related transporters) was prevented. Switching off cholesterol efflux, even in the presence of TO-901317, caused no change in Ab levels. However, when efflux capability was restored, TO-901317 reduced Ab levels. These data show that promoting cholesterol efflux is a viable target for Ab reducing strategies; however, knockout of cholesterol transporters is not sufficient to alter Ab in vitro or in vivo.
Entomopathogenic fungi can overcome insecticide resistance and represent promising tools for the control of mosquitoes. Better understanding of fungus-mosquito interactions is critical for improvement of fungal efficacy. Upon insect cuticle induction, pathogenic fungi undergo marked infection-related morphological differentiation. However, regulatory mechanisms of fungal infection–related morphogenesis are poorly understood. Here, we show that a histone lysine methyltransferase KMT2 in Metarhizium robertsii (MrKMT2) is up-regulated upon cuticle induction. MrKMT2 plays crucial roles in regulating infection-related morphogenesis and pathogenicity by up-regulating the transcription factor gene Mrcre1 via H3K4 trimethylation during mosquito cuticle infection. MrCre1 further regulates the cuticle-induced gene Mrhyd4 to modulate infection structure (appressorium) formation and virulence. Overall, the MrKMT2-MrCre1-MrHyd4 regulatory pathway regulates infection-related morphogenesis and pathogenicity in M. robertsii. These findings reveal that the epigenetic regulatory mechanism plays a pivotal role in regulating fungal pathogenesis in insects, and provide new insights into molecular interactions between pathogenic fungi and insect hosts.
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