pGluAβ increases accumulation of Aβ in vivo and exacerbates its toxicity

Several species of β-amyloid peptides (Aβ) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aβ peptides. Several N-terminal modified Aβ peptides have also been identified in Alzheimer’s disease (AD) brains, the most common of which is pyroglutamate-modified Aβ (AβpE3-42). AβpE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ1-42 deposition. Moreover, in vitro studies have shown that AβpE3-42 can act as a seed for full length Aβ1-42. In this study, we characterized the Drosophila model of AβpE3-42 toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AβpE3-42 peptide had an increased propensity to aggregate. Expression of AβpE3-42 in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AβpE3-42 constitutively in the eyes led to disorganised ommatidia, and activation of the c-Jun N-terminal kinase (JNK) signaling pathway. The eye disruption was almost completely rescued by co-expressing a candidate Aβ degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading AβpE3-42. Also, we tested the seeding hypothesis for AβpE3-42 in vivo, and measured its effect on Aβ1-42 levels. We found that Aβ1-42 levels were significantly increased when Aβ1-42 and AβpE3-42 peptides were co-expressed. Furthermore, we found that AβpE3-42 enhanced Aβ1-42 toxicity in vivo. Our findings implicate AβpE3-42 as an important source of toxicity in AD, and suggest that its specific degradation could be therapeuti

Ebi/AP-1 Suppresses Pro-Apoptotic Genes Expression and Permits Long-Term Survival of Drosophila Sensory Neurons

Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1) is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box–like and WD40 repeats–containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1) and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration

Epidemiological risk factors for adult dengue in Singapore: an 8-year nested test negative case control study

10.1186/s12879-016-1662-4BMC Infectious Diseases16132

The Astrocyte-Targeted Therapy by Bushi for the Neuropathic Pain in Mice

BACKGROUND: There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required. METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro. CONCLUSIONS: Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain

<i>ebi</i> downregulates <i>hid</i> expression via the AP-1 target site in the promoter region of <i>hid</i>.

<p>(A) Schematic of the promoter region of <i>hid</i>. The AP-1 half site and its mutant forms are indicated. (B) Luciferase constructs with different lengths of the promoter region of <i>hid</i>. Effects of <i>ebi</i> dsRNA on expression of the wild-type or mutant forms of <i>hid</i>-<i>luc</i> are shown in the graph. ** = p<0.01; # = p>0.05. Data are shown as the mean ± S.E.M.</p

<i>Jra</i> is required for <i>ebi</i>-dependent retinal degeneration.

<p>Eye sections of aged flies. (A) <i>GMR-ebiΔC</i>/<i>+; hid⁰⁵⁰¹⁴/+, (ebiΔC; hid</i>/+<i>)</i> ommatidia. 5 weeks after eclosion. (B) <i>GMR-ebiΔC/+; Df(3L)H99/+, (ebiΔC; H99/+)</i> ommatidia. 5 weeks after eclosion. (C, D) <i>GMR-ebiΔC</i>/<i>+; th⁴/+, (ebiΔC; th</i>/+<i>)</i> ommatidia. Eye sections of 2 days aged flies showed slight degeneration phenotype (C). One week aged flies showed severe degeneration phenotype (D). (E, F) Transmission electron microscope images of ommatidia. 5 weeks after eclosion. Wild-type flies had normal ommatidia, and each mitochondrion was arranged along the cell-cell junction with compact structures (E, inset). <i>ebiΔC</i> flies, in contrast, had electron-dense vesicles (arrows) and showed mitochondrial swelling and changes in mitochondrial cristae (F, inset). mt, mitochondrion; Ra, rhabdomere. (G) <i>GMR-ebiΔC</i>/<i>Jra¹, (ebiΔC; Jra</i>/+<i>)</i> ommatidia. 5 weeks after eclosion. (H) <i>hep^r75</i>/+; <i>GMR-ebiΔC</i>/+, <i>(hep</i>/+; <i>ebiΔC)</i> ommatidia. 5 weeks after eclosion.</p

Cellular Defense and Sensory Cell Survival Require Distinct Functions of <i>ebi</i> in <i>Drosophila</i>

<div><p>The innate immune response and stress-induced apoptosis are well-established signaling pathways related to cellular defense. NF-κB and AP-1 are redox-sensitive transcription factors that play important roles in those pathways. Here we show that Ebi, a <i>Drosophila</i> homolog of the mammalian co-repressor molecule transducin β-like 1 (TBL1), variously regulates the expression of specific genes that are targets of redox-sensitive transcription factors. In response to different stimuli, Ebi activated gene expression to support the acute immune response in fat bodies, whereas Ebi repressed genes that are involved in apoptosis in photoreceptor cells. Thus, Ebi seems to act as a regulatory switch for genes that are activated or repressed in response to different external stimuli. Our results offer clear <i>in vivo</i> evidence that the Ebi-containing co-repressor complex acts in a distinct manner to regulate transcription that is required for modulating the output of various processes during <i>Drosophila</i> development.</p></div