Aspirin-triggered resolvin D1 modulates pulmonary and neurological inflammation in an IL-22 knock-out organic dust exposure mouse model.

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues.

Immune cell infiltration and modulation of the blood-brain barrier in a guinea pig model of tuberculosis: Observations without evidence of bacterial dissemination to the brain.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is a chronic inflammatory disease. Although typically associated with inflammation of the lungs and other peripheral tissues, increasing evidence has uncovered neurological consequences attributable to Mtb infection. These include deficits in memory and cognition, increased risk for neurodegenerative disease, and progressive neuropathology.

Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.

Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.

Characterizing dog cognitive aging using spontaneous problem-solving measures: development of a battery of tests from the Dog Aging Project.

Companion dogs are a valuable model for aging research, including studies of cognitive decline and dementia. With advanced age, some dogs spontaneously develop cognitive impairments and neuropathology resembling features of Alzheimer's disease. These processes have been studied extensively in laboratory beagles, but the cognitive assays used in that context-which rely on time-consuming operant procedures-are not easily scalable to large samples of community-dwelling companion dogs.

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable.

Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.

Aim: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging.

Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission.

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable.

Effects of NCTC 11659 and Lipopolysaccharide Challenge on Polarization of Murine BV-2 Microglial Cells.

Previous studies have shown that the in vivo administration of soil-derived bacteria with anti-inflammatory and immunoregulatory properties, such as NCTC 11659, can prevent a stress-induced shift toward an inflammatory M1 microglial immunophenotype and microglial priming in the central nervous system (CNS). It remains unclear whether NCTC 11659 can act directly on microglia to mediate these effects. This study was designed to determine the effects of NCTC 11659 on the polarization of naïve BV-2 cells, a murine microglial cell line, and BV-2 cells subsequently challenged with lipopolysaccharide (LPS).

Adipose-Derived Mesenchymal Stromal Cells Co-Cultured with Primary Mixed Glia to Reduce Prion-Induced Inflammation.

Mesenchymal stromal cells (MSCs) are potent regulators of inflammation through the production of anti-inflammatory cytokines, chemokines, and growth factors. These cells show an ability to regulate neuroinflammation in the context of neurodegenerative diseases such as prion disease and other protein misfolding disorders. Prion diseases can be sporadic, acquired, or genetic; they can result from the misfolding and aggregation of the prion protein in the brain.

Biological agents and the aging brain: glial inflammation and neurotoxic signaling.

Neuroinflammation is a universal characteristic of brain aging and neurological disorders, irrespective of the disease state. Glial inflammation mediates this signaling, through astrocyte and microglial polarization from neuroprotective to neurotoxic phenotypes. Glial reactivity results in the loss of homeostasis, as these cells no longer provide support to neurons, in addition to the production of chronically toxic pro-inflammatory mediators.

Activated gliosis, accumulation of amyloid β, and hyperphosphorylation of tau in aging canines with and without cognitive decline.

Canine cognitive dysfunction (CCD) syndrome is a well-recognized naturally occurring disease in aged dogs, with a remarkably similar disease course, both in its clinical presentation and neuropathological changes, as humans with Alzheimer's disease (AD). Similar to human AD patients this naturally occurring disease is found in the aging canine population however, there is little understanding of how the canine brain ages pathologically. It is well known that in neurodegenerative diseases, there is an increase in inflamed glial cells as well as an accumulation of hyperphosphorylation of tau (P-tau) and amyloid beta (Aβ).

Gliosis, misfolded protein aggregation, and neuronal loss in a guinea pig model of pulmonary tuberculosis.

Tuberculosis, caused by infection, is an ongoing epidemic with an estimated ten million active cases of the disease worldwide. Pulmonary tuberculosis is associated with cognitive and memory deficits, and patients with this disease are at an increased risk for Parkinson's disease and dementia. Although epidemiological data correlates neurological effects with peripheral disease, the pathology in the central nervous system is unknown.

Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease.

Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this ability by stimulating MSCs with inflammatory molecules, improving their migratory and secretory properties. We investigated the use of intranasally delivered adipose-derived MSCs (AdMSCs) in combating prion disease in a mouse model.

Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro.

Prion diseases are characterized by the cellular prion protein, PrP, misfolding and aggregating into the infectious prion protein, PrP, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease.

Assessment of risk factors in dogs with presumptive advanced canine cognitive dysfunction.

Objectives: The aim of this study was to investigate the potential risk factors involved in the development of presumptive advanced canine cognitive dysfunction (pACCD).

Materials And Methods: A questionnaire was developed to identify dogs with presumptive canine cognitive dysfunction (CCD) based on an adapted Canine Dementia Scale and to evaluate for potential risk factors among the presumptive advanced cognitive dysfunction group. The questionnaire was distributed to 7,574 owners of dogs (≥8 years of age) who presented to the CSU VTH between 2017 and 2020.

Nontransgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer's Disease.

Older age is the primary risk factor for most chronic diseases, including Alzheimer's disease (AD). Current preclinical models to study brain aging and AD are mainly transgenic and harbor mutations intended to mirror brain pathologies associated with human brain aging/AD (eg, by increasing production of the amyloid precursor protein, amyloid beta [Aβ], and/or phosphorylated tau, all of which are key pathological mediators of AD). Although these models may provide insight on pathophysiological processes in AD, none completely recapitulate the disease and its strong age-dependence, and there has been limited success in translating preclinical results and treatments to humans.

Tissue-specific biochemical differences between chronic wasting disease prions isolated from free-ranging white-tailed deer (Odocoileus virginianus).

Chronic wasting disease (CWD) is an invariably fatal prion disease affecting cervid species worldwide. Prions can manifest as distinct strains that can influence disease pathology and transmission. CWD is profoundly lymphotropic, and most infected cervids likely shed peripheral prions replicated in lymphoid organs.

Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein.

Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids.

Network Simulations Reveal Molecular Signatures of Vulnerability to Age-Dependent Stress and Tau Accumulation.

Alzheimer's disease (AD) is the leading cause of dementia and one of the most common causes of death worldwide. As an age-dependent multifactorial disease, the causative triggers of AD are rooted in spontaneous declines in cellular function and metabolic capacity with increases in protein stressors such as the tau protein. This multitude of age-related processes that cause neurons to change from healthy states to ones vulnerable to the damage seen in AD are difficult to simultaneously investigate and even more difficult to quantify.

The cellular prion protein promotes neuronal regeneration after acute nasotoxic injury.

Adult neurogenesis, analogous to early development, is comprised of several, often concomitant, processes including proliferation, differentiation, and formation of synaptic connections. However, due to continual, asynchronous turn-over, newly-born adult olfactory sensory neurons (OSNs) must integrate into existing circuitry. Additionally, OSNs express high levels of cellular prion protein (PrP), particularly in the axon, which implies a role in this cell type.

Primary structural differences at residue 226 of deer and elk PrP dictate selection of distinct CWD prion strains in gene-targeted mice.

Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption of host prion protein (PrP) to its infective counterpart, contagious transmission of chronic wasting disease (CWD) results from shedding of prions produced at high titers in the periphery of diseased cervids. While deer and elk PrP primary structures are equivalent except at residue 226, which is glutamate in elk and glutamine in deer, the effect of this difference on CWD pathogenesis is largely unknown. Using a gene-targeting approach where the mouse PrP coding sequence was replaced with elk or deer PrP, we show that the resulting GtE226 and GtQ226 mice had distinct kinetics of disease onset, prion conformations, and distributions of prions in the brains of diseased mice following intracerebral CWD challenge.

Compensatory Expression of Nur77 and Nurr1 Regulates NF-B-Dependent Inflammatory Signaling in Astrocytes.

Inflammatory activation of glial cells promotes loss of dopaminergic neurons in Parkinson disease. The transcription factor nuclear factor κB (NF-B) regulates the expression of multiple neuroinflammatory cytokines and chemokines in activated glial cells that are damaging to neurons. Thus, inhibition of NF-B signaling in glial cells could be a promising therapeutic strategy for the prevention of neuroinflammatory injury.

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis.

Several complement proteins exacerbate prion disease, including C3, C1q, and CD21/35. These proteins of the complement cascade likely increase uptake, trafficking, and retention of prions in the lymphoreticular system, hallmark sites of early prion propagation. Complement regulatory protein factor H (fH) binds modified host proteins and lipids to prevent C3b deposition and, thus, autoimmune cell lysis.