Environmental and Anthropogenic Factors Shape the Skin Bacterial Communities of a Semi-Arid Amphibian Species.

The amphibian skin microbiome is important in maintaining host health, but is vulnerable to perturbation from changes in biotic and abiotic conditions. Anthropogenic habitat disturbance and emerging infectious diseases are both potential disrupters of the skin microbiome, in addition to being major drivers of amphibian decline globally. We investigated how host environment (hydrology, habitat disturbance), pathogen presence, and host biology (life stage) impact the skin microbiome of wild Dhofar toads (Duttaphrynus dhufarensis) in Oman. We detected ranavirus (but not Batrachochytrium dendrobatidis) across all sampling sites, constituting the first report of this pathogen in Oman, with reduced prevalence in disturbed sites. We show that skin microbiome beta diversity is driven by host life stage, water source, and habitat disturbance, but not ranavirus infection. Finally, although trends in bacterial diversity and differential abundance were evident in disturbed versus undisturbed sites, bacterial co-occurrence patterns determined through network analyses revealed high site specificity. Our results therefore provide support for amphibian skin microbiome diversity and taxa abundance being associated with habitat disturbance, with bacterial co-occurrence (and likely broader aspects of microbial community ecology) being largely site specific.

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases.

Latrepirdine (Dimebon(TM)) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the ß-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.

Olfactory discrimination predicts cognitive decline among community-dwelling older adults.

The presence of olfactory dysfunction in individuals at higher risk of Alzheimer's disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46-86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non-declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions using the Sniffin' Sticks battery indicated that, contrary to previous findings, olfactory discrimination, but not olfactory identification, significantly predicted subsequent cognitive decline (odds ratio = 0.869; P<0.05; 95% confidence interval = 0.764-0.988). The current study findings confirm previously reported associations between olfactory and cognitive functions, and indicate that impairment in olfactory discrimination can predict future cognitive decline. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia.

Effect of chronic hCG administration on Alzheimer's-related cognition and A beta accumulation in PS1KI mice.

Age-associated changes in the reproductive hormones-the gonadal steroid hormones and the gonadotropins-have been identified as potential risk factors for Alzheimer's disease (AD). However, levels of gonadotropins and estrogens are closely linked in vivo, and it has proven difficult to separate the effects of gonadotropins from the well-documented estrogenic effects on AD-related neuropathology in experimental models of menopause. To assess the effects of gonadotropins on cognition and AD biochemical markers independent of estrogenic effects, a potent analog of luteinizing hormone [human chorionic gonadotropin (hCG)] was administered to ovariectomized presenilin1 knock-in mice (PS1KI). Gonadotropin administration was found to induce hyperactivity and anxiety (Open Field Maze and Taste Neophobia Task) and working memory dysfunction, without altering reference memory (Morris Water Maze). Although gonadotropin administration modestly altered ß amyloid (Aß40) levels, levels of the longer more toxic form (Aß42) were unaffected. Furthermore, altered Aß40 levels were not associated with observed behavioral and cognitive impairments. These findings provide proof, in principle, that the gonadotropin hormones play a role in the modulation of AD-related behavior, cognition, and neuropathology.

Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic beta-amyloid (Abeta) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Abeta antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.

Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests.

Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-beta (Abeta) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Abeta is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Abeta leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Abeta are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Abeta clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Abeta ELISAs are discussed, as are the more promising results of Abeta imaging by positron emission tomography. Current knowledge of Abeta-binding proteins and Abeta-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Abeta remains an attractive therapeutic strategy, and improved understanding of Abeta clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease.

The relationship between menopause and cognitive decline has been the subject of intense research since a number of studies have shown that hormone replacement therapy could reduce the risk of developing Alzheimer's disease in women. In contrast, research into andropause has only recently begun. Furthermore, evidence now suggests that steroidogenesis is not restricted to the gonads and adrenals, and that the brain is capable of producing its own steroid hormones, including testosterone and estrogen. Sex hormones have been demonstrated to be of critical importance in the embryonic development of the central nervous system (CNS); however, we are only just beginning to understand the role that these hormones may play in the normal functioning and repair of the adult mammalian CNS. This review will summarize current research into the role of androgens and andropause on cognition and the possible mechanisms of action of androgens, with particular reference to Alzheimer's disease.

Chronic gliosis triggers Alzheimer's disease-like processing of amyloid precursor protein.

Alzheimer's disease is a progressively dementing illness characterized by the extracellular accumulation and deposition of beta-amyloid. Early onset Alzheimer's disease is linked to mutations in three genes, all of which lead to increased beta-amyloid production. Inflammatory changes and gliosis may also play a role in the disease process, but the importance of these reactive events remains unclear. We recently reported that chronic cortical gliosis in heterotopic fetal rat cortical transplants is associated with significant changes in the levels of some of the proteins implicated in the pathogenesis of Alzheimer's disease. Because rodent beta-amyloid does not form extracellular amyloid deposits, we have now extended this model of chronic cortical gliosis to transgenic mice expressing the Swedish mutant form of human amyloid precursor protein. In addition, apolipoprotein E knockout mice were used to elucidate the role of this protein in reactive gliosis. The expression of mutant and murine proteins was assayed 6 or 10 months after transplantation using immunohistochemical and western blot methods. Heterotopic transplantation of fetal cortex onto the midbrain of neonatal mice consistently resulted in reactive gliosis, independent of apolipoprotein E status. In contrast, in homotopic cortex-to-cortex grafts there was little alteration in glial reactivity, a result similar to that obtained previously in rats. By 10 months post-transplantation the level of presenilin-1 expression was lower in heterotopic grafts than in host cortex and there was increased expression of transgenic amyloid precursor protein, but only in the gliotic cortex-to-midbrain grafts. Most importantly, increased levels of beta-amyloid, and particularly its precursor, C-99, were selectively found in these heterotopic transplants. Our results show that chronic gliosis is associated with altered processing of the amyloid precursor protein in vivo and thus may initiate or exacerbate pathological changes associated with Alzheimer's disease.

Altered expression of apolipoprotein E, amyloid precursor protein and presenilin-1 is associated with chronic reactive gliosis in rat cortical tissue.

A major characteristic feature of Alzheimer's disease is the formation of compact, extracellular deposits of beta-amyloid (senile plaques). These deposits are surrounded by reactive astrocytes, microglia and dystrophic neurites. Mutations in three genes have been implicated in early-onset familial Alzheimer's disease. However, inflammatory changes and astrogliosis are also believed to play a role in Alzheimer's pathology. What is unclear is the extent to which these factors initiate or contribute to the disease progression. Previous rat studies demonstrated that heterotopic transplantation of foetal cortical tissue onto the midbrain of neonatal hosts resulted in sustained glial reactivity for many months. Similar changes were not seen in cortex-to-cortex grafts. Using this model of chronic cortical gliosis, we have now measured reactive changes in the levels of the key Alzheimer's disease proteins, namely the amyloid precursor protein, apolipoprotein E and presenilin-1. These changes were visualised immunohistochemically and were quantified by western blot analysis. We report here that chronic cortical gliosis in the rat results in a sustained increase in the levels of apolipoprotein E and total amyloid precursor protein. Reactive astrocytes in heterotopic cortical grafts were immunopositive for both of these proteins. Using a panel of amyloid precursor protein antibodies we demonstrate that chronic reactive gliosis is associated with alternative cleavage of the peptide. No significant changes in apolipoprotein E or amyloid precursor protein expression were seen in non-gliotic cortex-to-cortex transplants. Compared to host cortex, the levels of both N-terminal and C-terminal fragments of presenilin-1 were significantly lower in gliotic heterotopic grafts.The changes described here largely mirror those seen in the cerebral cortex of humans with Alzheimer's disease and are consistent with the proposal that astrogliosis may be an important factor in the pathogenesis of this disease.

Gaussian beams from variable groove depth grating couplers in planar waveguides.

Analysis, fabrication, and characterization of variable groove depth planar waveguide grating couplers are presented. A formula is derived to describe the grating groove depth variation necessary to produce an outcoupled beam of arbitrary profile. A variable depth grating for producing a Gaussian beam profile is fabricated on a waveguide by ion-beam etching through a scanning slit apparatus. A photoresist grating placed on the waveguide provides a mask to define the grating etched onto the waveguide. The near-field irradiance of the outcoupled beam is measured and shown to approach a Gaussian profile.

Design and fabrication of a single leakage-channel grating coupler.

We describe the modeling and fabrication of waveguide grating couplers with theoretical outcoupling efficiencies into a single diffracted order nearing 100%. Termed single leakage-channel grating couplers (or SLCGC's), these devices utilize a high-reflectivity dielectric stack to reflect the outcoupled beam diffracted toward the substrate and back up into the air region, where it constructively adds with the beam diffracted into the air region. Computer modeling shows that the branching ratio and the leakage rate can be independently controlled, and that the branching ratio is independent of grating depth and grating period. A SLCGC with a branching ratio of 97.1% is fabricated by the use of a combination of vacuum-evaporation and wet-chemical techniques.