Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system

The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor α and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults

Estrogen Receptor Transrepresses Brain Inflammation

Estrogen receptors (ERs) have long been implicated in the etiology of multiple sclerosis, but no clear molecular mechanisms have linked ERs to the disease's pathology. Now Saijo et al. (2011) provide evidence that ERβ activates a transrepression pathway that suppresses inflammation and inhibits progression of pathology in a mouse model of multiple sclerosis

MicroRNA-298 and MicroRNA-328 regulate expression of mouse ß-Amyloid precursor protein-converting enzyme 1

MicroRNAs (miRNAs) are key regulatory RNAs known to repress mRNA translation through recognition of specific binding sites located mainly in their 3′-untranslated region (UTR). Loss of specific miRNA control of gene expression is thus expected to underlie serious genetic diseases. Intriguingly, previous post-mortem analyses showed higher β-amyloid precursor protein-converting enzyme (BACE) protein, but not mRNA, levels in the brain of patients that suffered from Alzheimer disease (AD). Here we also observed a loss of correlation between BACE1 mRNA and protein levels in the hippocampus of a mouse model of AD. Consistent with an impairment of miRNA-mediated regulation of BACE1 expression, these findings prompted us to investigate the regulatory role of the BACE1 3′-UTR element and the possible involvement of specific miRNAs in cultured neuronal (N2a) and fibroblastic (NIH 3T3) cells. Through various experimental approaches, we validated computational predictions and demonstrated that miR-298 and miR-328 recognize specific binding sites in the 3′-UTR of BACE1 mRNA and exert regulatory effects on BACE1 protein expression in cultured neuronal cells. Our results may provide the molecular basis underlying BACE1 deregulation in AD and offer new perspectives on the etiology of this neurological disorder

MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with brain innate immune activation mainly mediated by microglia. These cells are known to be activated in the brain of AD patients and to produce inflammatory cytokines and neurotoxic molecules in response to Amyloid beta (Aβ). Activation of microglia can also promote Aβ clearance via Toll-like receptors (TLRs). Myeloid differentiation factor 88 (MyD88) is the adaptor molecule for most of these innate immune receptors, transducing the intracellular signal from TLRs to nucleus.</p> <p>Results</p> <p>Here, we report that more than 50% reduction in MyD88 expression in a mouse model of AD accelerated spatial learning and memory deficits. Brain of APP_swe/PS1-MyD88^+/-mice was characterized by a delay in accumulation of Aβ plaques and increased soluble levels of Aβ oligomers. Furthermore, inflammatory monocyte subset and brain IL-1β gene expression were significantly reduced in APP_swe/PS1 mice with impaired MyD88 signaling.</p> <p>Conclusions</p> <p>These data indicate that activation of MyD88 intracellular signaling pathway, likely by TLRs, acts as a natural innate immune mechanism to restrict disease progression of APP_swe/PS1 mice.</p

New Therapeutic Avenues of mCSF for Brain Diseases and Injuries

Macrophage colony-stimulating factor (mCSF) is a cytokine known to promote the recruitment of macrophages inducing the release of CCL2, a chemokine mobilizing monocytes to sites of inflammation. Additionally, it induces microglia/macrophage proliferation and the polarization of these cells towards a M2-like phenotype, impairing their ability to release pro-inflammatory factors and toxic mediators, while favoring the release of mediators promoting tissue repair. Another important player is the mCSF receptor CSFR1, which is highly expressed in monocytes, macrophages and microglia. Here, we discuss the new interesting therapeutic avenue of the mCSF/CSFR1 axis on brain diseases. More specifically, mCSF cascade might stimulate the survival/proliferation of oligodendrocytes, enhance the immune response as well as modulate the release of growth factors and the phagocytic activity of immune cells to remove myelin debris and toxic proteins from the brain

Calving photocensus of the Rivière George Caribou Herd and comparison with an independent census

Vertical photographs of the calving grounds have been used since 1984 to estimate the caribou (Rangifer tarandus) population of the Rivi&egrave;re George Caribou Herd (RGCH) in Northern Qu&eacute;bec and Labrador. In spite of large confidence intervals, the 1984 and 1988 estimates suggested that the herd stabilized at more than 650 000 caribou (fall estimate including calves) making the RGCH the largest caribou herd in the world. Between 1984 and 1990, studies suggested that the former rapid growth of the herd deteriorated the calving and summer habitats. This poor habitat quality affected physical condition, pregnancy rate and calf survival. It was important to have a valid estimate of the herd size and a photocensus was done in June 1993. Contrary to previous censuses, a slightly different sampling design was applied in 1993. Two methods were used to estimate the number of females in the June population. In the first method, the number of females was derived from the estimated number of calves on the photographs and from the June female/calf ratio. The second method was used in the previous census and is based on the number of adults on the photos and on the June female/adult ratio. It is suggested that the first method of estimating female abundance in June is better due to sampling problems associated with a strong adult sex segregation during calving. From the first method, the herd size in October 1993 was estimated at 583 829 adults (&plusmn;33.79%) and at 749 869 caribou including calves (&plusmn;33.15%) while the second method provided estimates of 764 221 adults (&plusmn;23.55%) and 981 565 caribou including calves (&plusmn;22.64%). It was possible to compare those population estimates with an independent census. In July 1993, an oblique photocensus of the post-calving aggregations was conducted by Russell et al. (1996). A new analysis of their raw data provided an estimate of 608 384 adults (&plusmn;14.35%). Both estimates from the June and July photocensus were combined. From the first and second method respectively, combined herd size estimates were 775 891 (&plusmn;13.40%) and 823 375 (&plusmn;12.36%) caribou including calves. The management implications are discussed and it is emphasized that the herd is still underharvested

SoK: Why Johnny Can't Fix PGP Standardization

Pretty Good Privacy (PGP) has long been the primary IETF standard for encrypting email, but suffers from widespread usability and security problems that have limited its adoption. As time has marched on, the underlying cryptographic protocol has fallen out of date insofar as PGP is unauthenticated on a per message basis and compresses before encryption. There have been an increasing number of attacks on the increasingly outdated primitives and complex clients used by the PGP eco-system. However, attempts to update the OpenPGP standard have failed at the IETF except for adding modern cryptographic primitives. Outside of official standardization, Autocrypt is a "bottom-up" community attempt to fix PGP, but still falls victim to attacks on PGP involving authentication. The core reason for the inability to "fix" PGP is the lack of a simple AEAD interface which in turn requires a decentralized public key infrastructure to work with email. Yet even if standards like MLS replace PGP, the deployment of a decentralized PKI remains an open issue

mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis

A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes