Johnson, W. Evan

Abstract We have previously reported the therapeutic effect of depletion and regeneration of endogenous microglia on autism spectrum disorder-like behaviors in offspring from the dams under maternal immune activation (MIA) by dampening their neuritogenic activation. Here we show a long-lasting pathological effect by MIA, leading to abnormal behaviors in offspring mice in a sex-specific manner at 3 months of age. MIA was induced by injecting Polyinosinic:polycytidylic acid [Poly(I:C)] at 10mg/kg at E9.5 with preselected dams based on the immunoreactivity to low-dose Poly(I:C) injection. MIA offspring show impairments in sociability, repetitive behavior, and spatial working and associative memories in both sexes, whereas only male offspring show social novelty deficit. MIA has no effect on anxiety-like behavior nor sensori-motor or locomotor activity. Administering colony stimulating factor receptor (CSF1R) inhibitor in young adult MIA offspring regenerates microglia and ameliorates sociability deficits in males and spatial working and associative memory impairments in both sexes without effect on social novelty impairments. Transcriptomic analysis of prefrontal cortex and hippocampal tissues reveals MIA and sex-specific pathways and highlights potential key genes involved in the corrective effect of microglial regeneration in MIA offspring. Our results underscore the potential of the sex-specific therapeutic applications of CSF1R inhibitor for MIA-related social and cognitive disorders.

Wolframin-1–positive neurons in the entorhinal cortex of mouse brain propagate tau to the hippocampal CA1 region resulting in memory impairment.

Abstract Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©2016 AACR.