The impact of mild episodic ketosis on microglia and hippocampal long-term depression in 5xFAD mice.

Ketotherapeutics is a potential metabolic intervention for mitigating dementias; however, its mechanisms and optimal methods of application are not well understood. Our previous in vitro study showed that β-hydroxybutyrate (BHB), a major ketone body, reverses pathological features of amyloid-β oligomer (AβO)-activated microglia. Here we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer's disease (AD) mouse model.

Unique N-glycosylation signatures in Aβ oligomer-and lipopolysaccharide-activated human iPSC-derived microglia.

Microglia are the immune cells in the central nervous system (CNS) and become pro-inflammatory/activated in Alzheimer's disease (AD). Cell surface glycosylation plays an important role in immune cells; however, the N-glycosylation and glycosphingolipid (GSL) signatures of activated microglia are poorly understood. Here, we study comprehensive combined transcriptomic and glycomic profiles using human induced pluripotent stem cells-derived microglia (hiMG).

Effects of Sex and Western Diet on Spatial Lipidomic Profiles for the Hippocampus, Cortex, and Corpus Callosum in Mice Using MALDI MSI.

Diet is inextricably linked to human health and biological functionality. Reduced cognitive function among other health issues has been correlated with a western diet (WD) in mouse models, indicating that increases in neurodegeneration could be fueled in part by a poor diet. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to spatially map the lipidomic profiles of male and female mice that were fed a high-fat, high-sucrose WD for a period of 7 weeks.

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1.

The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia.

Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied.

Transcriptomic and glycomic analyses highlight pathway-specific glycosylation alterations unique to Alzheimer's disease.

Glycosylation has been found to be altered in the brains of individuals with Alzheimer's disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD.

The role of FUT8-catalyzed core fucosylation in Alzheimer's amyloid-β oligomer-induced activation of human microglia.

Fucosylation, especially core fucosylation of N-glycans catalyzed by α1-6 fucosyltransferase (fucosyltransferase 8 or FUT8), plays an important role in regulating the peripheral immune system and inflammation. However, its role in microglial activation is poorly understood. Here we used human induced pluripotent stem cells-derived microglia (hiMG) as a model to study the role of FUT8-catalyzed core fucosylation in amyloid-β oligomer (AβO)-induced microglial activation, in view of its significant relevance to the pathogenesis of Alzheimer's disease (AD).

Mechanical Cues for Triggering and Regulating Cellular Movement Selectively at the Single-Cell Level.

Cell motility plays important roles in many biophysical and physiological processes ranging from in vitro biomechanics, wound healing, to cancer metastasis. This work introduces a new means to trigger and regulate motility individually using transient mechanical stimulus applied to designated cells. Using BV2 microglial cells, our investigations indicate that motility can be reproducibly and reliably initiated using mechanical compression of the cells.

Intestinal Microbiota Remodeling Protects Mice from Western Diet-Induced Brain Inflammation and Cognitive Decline.

It has been shown that the Western diet (WD) induces systemic inflammation and cognitive decline. Moreover, probiotic supplementation and antibiotic treatment reduce diet-induced hepatic inflammation. The current study examines whether shaping the gut microbes by () supplementation and antibiotic treatment reduce diet-induced brain inflammation and improve neuroplasticity.

Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function.

Background: Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition.

Methods: C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning.

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4-mediated calcium entry in microglia.

Microglia-mediated inflammation exerts adverse effects in ischemic stroke and in neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the voltage-gated potassium channel Kv1.3 is required for microglia activation.

Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease.

Objective: Microglia play a pivotal role in the initiation and progression of Alzheimer's disease (AD). We here tested the therapeutic hypothesis that the Ca-activated potassium channel KCa3.1 constitutes a potential target for treating AD by reducing neuroinflammation.

The voltage-gated potassium channel Kv1.3 is required for microglial pro-inflammatory activation in vivo.

Microglia show a rich repertoire of activation patterns regulated by a complex ensemble of surface ion channels, receptors, and transporters. We and others have investigated whether microglia vary their K channel expression as a means to achieve functional diversity. However, most of the prior studies were conducted using in vitro models such as BV2 cells, primary microglia, or brain slices in culture, which may not accurately reflect microglia physiology in adult individuals.

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity.

The goal of this study was to identify the intrinsic links that explain the effect of a Western diet (WD) on cognitive dysfunction. Specific pathogen-free, wild-type mice were fed either a control diet (CD) or a high-fat, high-sucrose WD after weaning and were euthanized at 10 mo of age to study the pathways that affect cognitive health. The results showed that long-term WD intake reduced hippocampal synaptic plasticity and the level of brain-derived neurotrophic factor mRNA in the brain and isolated microglia.

Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept.

Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.

Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output.

The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule.

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions.

Characteristics of pectinase treated with ultrasound both during and after the immobilization process.

In this study, ultrasound was applied both during and after the immobilization process and characteristics of different immobilized pectinase samples were studied. When introduced during the immobilization process, ultrasound at an intensity of 9WmL for 20min increased the immobilization yield 92.28% more than the control.

An examination of sources of sensitivity of consumer surplus estimates in travel cost models.

We examine sensitivity of estimates of recreation demand using the Travel Cost Method (TCM) to four factors. Three of the four have been routinely and widely discussed in the TCM literature: a) Poisson verses negative binomial regression; b) application of Englin correction to account for endogenous stratification; c) truncation of the data set to eliminate outliers. A fourth issue we address has not been widely modeled: the potential effect on recreation demand of the interaction between income and travel cost.

Evidence of population-level lateralized behaviour in giant water bugs, Belostoma flumineum Say (Heteroptera: Belostomatidae): T-maze turning is left biased.

Lateralized behaviour occurs in diverse animals, but relatively few studies examine the phenomenon in invertebrates. Here we report a population-level left turn bias in the giant water bug Belostoma flumineum Say (Heteroptera: Belostomatidae) in an underwater T-maze. Individuals made significantly more left turns than right turns, including when they were naïve and first introduced to the maze.

Reintegration success of osseotite implants after intentional countertorque liberation in the endentulous human mandible.

Purpose: Implants that rotate during abutment screw tightening may not necessarily constitute implant failure. This prospective study was designed to determine to what degree integrated implants could gain a state of reintegration after intentional countertorque to liberation from the bone.

Materials And Methods: There were 11 patients with fully edentulous mandibles restored with 2 "clinical" implants (3.

Autonomic efferents affect intake of imbalanced amino acid diets by rats.

An anorectic response occurs following ingestion of imbalanced amino acid (IMB) diets. There are three phases to this response: 1, recognition of the IMB diet; 2, conditioned development of an aversion to the IMB diet; and 3, adaptation. Blockade of peripheral serotonin-3 (5-HT3) receptors or vagotomy attenuates Phase 2 of the anorectic response.

Differential effects of selective vagotomy and tropisetron in aminoprivic feeding.

Both total subdiaphragmatic vagotomy (TVAGX) and serotonin(3) receptor blockade with tropisetron or ondansetron attenuate amino acid-imbalanced diet (Imb) anorexia. Total vagotomy is less effective than tropisetron in reducing Imb-induced anorexia and also blunts the tropisetron effect. With the use of electrocautery at the subdiaphragmatic level of the vagus, we severed the ventral and dorsal trunks as well as the hepatic, ventral gastric, dorsal gastric, celiac, and accessory celiac branches separately or in combination to determine which vagal branches or associated structures may be involved in these responses.