Okun, E. | bioRxiv Science

bioRxiv2020

Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

Down Syndrome (DS) features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Amyloid-{beta} (A{beta}) overproduction and tau hyper-phosphorylation. As DS can be diagnosed in utero, maternally transferred anti-A{beta} antibodies might promote removal of early accumulation of A{beta} from the CNS. A DNA-vaccine expressing A{beta}1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early A{beta} plaque formation, similar to individuals with DS. Maternal A{beta}-specific antibodies provided transgenic offspring with passive immunization against A{beta} via the placental and subsequently lactation. Maternal antibodies reduced cortical A{beta} levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits and activation of the Fc{gamma}R1/Syk/Cofilin pathway in microglia. Sera from immunized dams facilitated A{beta} clearance by microglia in a Syk-dependent manner. These data suggest that maternal anti-A{beta} immunization is a potential strategy to alleviate cognitive decline in individuals with DS.

neuroscience↗

bioRxiv2020

Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

Intermittent fasting (IF) is a lifestyle intervention comprising a dietary regimen in which energy intake is restricted via alternating periods of fasting and ad libitum food consumption, without compromising nutritional composition. While epigenetic modifications can mediate effects of environmental factors on gene expression, no information is yet available on potential effects of IF on the epigenome. In this study, we found that IF causes modulation of histone H3 lysine 9 trimethylation (H3K9me3) epigenetic mark in the cerebellum of male C57/BL6 mice, which in turn orchestrates a plethora of transcriptomic changes involved in the robust metabolic switching processes commonly observed during IF. Interestingly, both epigenomic and transcriptomic modulation continued to be observed after refeeding, suggesting that memory of the IF-induced epigenetic change is maintained at the locus. Notably though, we found that termination of IF results in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes a novel mechanism of IF in the epigenetic-transcriptomic axis, which controls myriad metabolic process changes. In addition to providing a valuable and innovative resource, our systemic analyses reveal molecular framework for understanding how IF impacts the metaboloepigenetics axis of the brain. Highlights{circ} Intermittent fasting (IF) and refeeding modifies epigenome in the cerebellum {circ}Integrative epigenomic and transcriptomic analyses revealed metabolic switching {circ}IF affects the metaboloepigenetics axis in regulating metabolic processes {circ}Integrative analyses revealed a loss of epigenetic reprogramme following refeeding

neuroscience↗