第774回 千葉医学会例会・第二内科例会 64.

The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 μM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRβ, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 μM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists

A sheep in wolf's clothing : levels of deceit and detection in the evolution of communication

Trivers has hypothesized that self-deception in our species has evolved for the better deception of others: in an arms race between deception and deception-detection, the dishonest individuals evolve ever-more complex trickery and the deceived an ever-more refined ability to distinguish honesty from deception. Detection at some point becomes so precise that a degree of self-deception can evolve to avoid emitting secondary cues that otherwise give away the deceit. In an attempt to formalize this, we focus on aspects of self-deception that can be generalized to non-humans, as human self-deception by itself relies on concepts that are difficult to define or to apply to other organisms. We formally explore one central aspect of Trivers' hypothesis: the evolution of costly and well-integrated or deep deceptive morphs that span multiple signals and cues. We demonstrate that the depth of deception in a communicative interaction is correlated with the number of signals detected, the cost of errors in judgment for signal detectors, and the benefits of successful deception. We also show that the frequency of well-integrated deceptive strategies is highest when the cost of errors in judgment is high and the cost of detection of other less well-integrated forms of deception is low. These results may partially explain variation in deception in nature and provide researchers with predictions that can be tested empirically, with obvious implications for self-deception. Moreover, we argue that self-deception under Trivers' hypothesis is the product of a hierarchical system, in this case, the cognitive system, with some parts (ex. the subconscious) controlling and ultimately manipulating the information that is received by other parts (ex. the conscious). Although we do not model this, we emphasize that hierarchies are integral parts of many systems such as gene regulatory networks. Thus, in response to an arms race with an adversary, these hierarchies can potentially evolve ``internal deception'', with some parts transmitting manipulated information to other parts to prevent information leakage. We argue that modeling how properties of hierarchies affect the evolution of deception can allow for testable predictions and a better understanding of deception and self-deception in general.Science, Faculty ofZoology, Department ofGraduat

Chronic Exposure to Androgenic-Anabolic Steroids Exacerbates Axonal Injury and Microgliosis in the CHIMERA Mouse Model of Repetitive Concussion

<div><p>Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8–16 weeks of age. At the end of the 7^th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.</p></div

Chronic AAS treatment in mice augments post-rTBI microgliosis.

<p>Post-rTBI microglial activation was assessed with Iba1 immunohistochemistry at 7 d. Representative 40X-magnified images of white matter regions show resting microglia in sham brains (left column) and activated microglia in injured brains (second and third columns).</p

Chronic AAS treatment in mice exacerbates post-rTBI axonal injury.

<p>Post-rTBI axonal damage was assessed with silver staining. Representative 40X-magnified images of corpus callosum, external capsule, septal-fimbrial area and optic tract of sham (left column) and VH- (middle column) and AAS-treated (right column) rTBI brains are depicted.</p

Quantitative assessment of silver stained images.

<p>Silver stained images were quantified by calculating the percent of region of interest (ROI) in the white matter tract area that was stained with silver. Graphs indicate percent of the ROI showing positive signal in the respective white matter regions. For all graphs, * indicates a significant rTBI effect compared to the respective sham values and # indicates a significant treatment effect between rTBI groups. Data are analyzed by two-way ANOVA followed by a Tukey post-hoc test. For all graphs **: <i>p</i> < 0.01, ***: <i>p</i> < 0.001, ****: <i>p</i> < 0.0001, #: <i>p</i> < 0.05, ##: <i>p</i> < 0.01, ###: <i>p</i> < 0.001.</p

Chronic AAS treatment does not exacerbate acute post-rTBI behavioral deficits.

<p>(A) Duration of loss of righting reflex (LRR) was assessed immediately following the sham or TBI procedure. (B) Composite neurological severity score (NSS) was assessed at 1 h and at 1, 2 and 7 d post-rTBI. (C) Motor performance was assessed on an accelerating rotarod at 1, 2, and 7 d post-rTBI. The graph depicts fall latency in seconds at baseline before rTBI and at three post-rTBI time points. (D) Thigmotaxis was quantified at 1 and 6 d post-rTBI and is represented as thigmotaxis index. (E) Aggressive behavior was assessed with the RIT at the 5^th (RIT # 1) and 6^th (RIT # 2) week following initiation of AAS treatment (pre-rTBI) as well as at 5 d (RIT # 3) post-rTBI. Graphs represent latency to initiate fighting by the resident mouse. Data in all graphs are presented as mean ± SEM. Data are analyzed by repeated measures general linear model. Legends and cohort sizes are consistent across all graphs.</p

Chronic AAS treatment downregulates 5-HT1B receptor expression in the substantia nigra.

<p>Immunohistochemistry was used to assess 5-HT1B receptor expression levels. Representative images of whole-mount sections for AAS-treated and control brains are depicted in Panel A. 5-HT1B receptor expression in the substantia nigra (dashed circles) was quantified by measuring the mean grey intensity of the selected brain area on an 8-bit grayscale image. Graph in Panel B depicts mean staining intensity in arbitrary units.</p