Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease.

Background And Purpose: Activation of type 2 imidazoline receptors has been shown to exhibit neuroprotective properties including anti-apoptotic and anti-inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the imidazoline-2 ligand BU224 in a model of amyloidosis.

Experimental Approach: Six-month-old female transgenic 5XFAD and wild-type (WT) mice were treated intraperitoneally with 5-mg·kg BU224 or vehicle twice a day for 10 days.

Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease.

The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP-TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes.

The amyloid precursor protein binds to β-catenin and modulates its cellular distribution.

Accumulating evidence has shown that the processing of the amyloid precursor protein (APP) and the formation of amyloid-β are associated with the canonical Wnt/ β-catenin signalling pathway. It was recently published that the drosophila homologue of APP is a conserved modulator of Wnt PCP signalling, suggesting a potential regulation of this pathway by APP. The aim of this study was to investigate the potential interaction of APP with the canonical Wnt pathway.

Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline.

Environmental manipulations enhance neuroplasticity, with enrichment-induced cognitive improvements linked to increased expression of growth factors and enhanced hippocampal neurogenesis. Environmental enrichment (EE) is defined as the addition of social, physical and somatosensory stimulation into an animal's environment via larger group housing, extra objects and, often, running wheels. Previous studies from our laboratory report that physical activity is a potent memory enhancer but that long-term environmental stimulation can be as effective as exercise at ameliorating age-related memory decline.

Higher order intentionality tasks are cognitively more demanding.

A central assumption that underpins much of the discussion of the role played by social cognition in brain evolution is that social cognition is unusually cognitively demanding. This assumption has never been tested. Here, we use a task in which participants read stories and then answered questions about the stories in a behavioural experiment (39 participants) and an fMRI experiment (17 participants) to show that mentalising requires more time for responses than factual memory of a matched complexity and also that higher orders of mentalising are disproportionately more demanding and require the recruitment of more neurons in brain regions known to be associated with theory of mind, including insula, posterior STS, temporal pole and cerebellum.

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer's disease model.

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients.

Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice.

There is an emerging evidence that growth factors may have a potential beneficial use in the treatment of Alzheimer's disease (AD) because of their neuroprotective properties and effects on neuronal proliferation. Basic fibroblast growth factor or fibroblast growth factor-2 (FGF2) is an anti-inflammatory, angiogenic, and neurotrophic factor that is expressed in many cell types, including neurons and glial cells. Here, we explored whether subcutaneous administration of FGF2 could have therapeutic effects in the APP 23 transgenic mouse, a model of amyloid pathology.

The contribution of astrocytes to Alzheimer's disease.

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD.

Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime.

Study Objective: To evaluate the observed incidence of acute kidney injury (AKI) in adult patients receiving either piperacillin-tazobactam and vancomycin or cefepime-vancomycin for more than 48 hours.

Design: Retrospective matched cohort.

Setting: Large academic medical center.

Modulation of inflammation in transgenic models of Alzheimer's disease.

Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies.

Chronic intracerebroventricular infusion of nerve growth factor improves recognition memory in the rat.

Nerve Growth Factor (NGF) plays pivotal roles in neuronal survival in the adult mammalian brain and may modulate forms of structural and functional plasticity, including neurogenesis. We have shown previously that six weeks of housing in an enriched environment (EE) that did not include access to running wheels resulted in improved recognition memory concomitant with increased NGF expression and neurogenesis in the hippocampus. Here we have attempted to probe a causal link between NGF and the observed enrichment-induced changes in hippocampal function by assessing the effects of six weeks continuous intracerebroventricular (i.

Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner.

Environmental manipulations can enhance neuroplasticity in the brain, with enrichment-induced cognitive improvements being linked to increased expression of growth factors, such as neurotrophins, and enhanced hippocampal neurogenesis. There is, however, a great deal of variation in environmental enrichment protocols used in the literature, making it difficult to assess the role of particular aspects of enrichment upon memory and the underlying associated mechanisms. This study sought to evaluate the efficacy of environmental enrichment, in the absence of exercise, as a cognitive enhancer and assess the role of Nerve Growth Factor (NGF), neurogenesis and synaptogenesis in this process.

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability.

In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity.

Effects of lipophilic components on the compatibility of lipid-based formulations with hard gelatin capsules.

The present study investigated the effect of lipophilic components on the compatibility of propylene glycol (PG)-containing lipid-based drug delivery system (LBDDS) formulations with hard gelatin capsules. The presence of a lipophilic active pharmaceutical ingredient (API) (log P approximately 6.1) and an additional lipophilic excipient (Capmul MCM) significantly affected the activity of PG in the fills and the equilibrium of PG between capsule shells and fills.

Exercise enhances hippocampal-dependent learning in the rat: evidence for a BDNF-related mechanism.

Short periods of forced exercise have been reported to selectively induce enhancements in hippocampal-dependent cognitive function, possibly via brain-derived neurotrophic factor (BDNF)-mediated mechanisms. In this study, we report that 1 week of treadmill running significantly enhanced both object displacement (spatial) and object substitution (nonspatial) learning. These behavioral changes were accompanied by increased expression of BDNF protein in the dentate gyrus, hippocampus, and perirhinal cortex.