Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a severe neurodegenerative condition that affects millions of people worldwide. The TgF344 AD rat model, which exhibits early depression-like behavior followed by later cognitive impairment, is widely used to evaluate putative biomarkers and potential treatments for AD. The P7C3 neuroprotective compounds have shown protective efficacy for both brain pathology and neuropsychiatric impairment in this model.

Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer's disease.

Alzheimer's disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined.

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months.

(-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia.

Background: In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people.

Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice.

Axonal degeneration is a prominent feature of many forms of neurodegeneration, and also an early event in blast-mediated traumatic brain injury (TBI), the signature injury of soldiers in Iraq and Afghanistan. It is not known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. The Wallerian degeneration slow strain () of mice is resistant to some forms of axonal degeneration because of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1).

P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.

The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage.

Endothelial Von Willebrand factor promotes blood-brain barrier flexibility and provides protection from hypoxia and seizures in mice.

Objective: Aberrant blood-brain barrier (BBB) permeability is a hallmark pathology of many central nervous system diseases. von Willebrand factor (VWF) is stored in endothelial Weibel-Palade bodies from where it is released on activation into plasma and basement membrane. The role of VWF in endothelial homeostasis is unclear.

Lack of tryptophan hydroxylase-1 in mice results in gait abnormalities.

The role of peripheral serotonin in nervous system development is poorly understood. Tryptophan hydroxylase-1 (TPH1) is expressed by non-neuronal cells including enterochromaffin cells of the gut, mast cells and the pineal gland and is the rate-limiting enzyme involved in the biosynthesis of peripheral serotonin. Serotonin released into circulation is taken up by platelets via the serotonin transporter and stored in dense granules.

Assessing multiple endpoints of atrazine ingestion on gravid Northern Watersnakes (Nerodia sipedon) and their offspring.

Ecotoxicological studies that focus on a single endpoint might not accurately and completely represent the true ecological effects of a contaminant. Exposure to atrazine, a widely used herbicide, disrupts endocrine function and sexual development in amphibians, but studies involving live-bearing reptiles are lacking. This study tracks several effects of atrazine ingestion from female Northern Watersnakes (Nerodia sipedon) to their offspring exposed in utero.

Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis.

Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic.

ADAMTS13 exerts a thrombolytic effect in microcirculation.

Recombinant tissue plasminogen activator (r-tPA) is the drug of choice for thrombolysis, but it is associated with a significant risk of bleeding and is not always successful. By cleaving von Willebrand factor (VWF), the metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) down-regulates thrombus formation in injured vessels. We investigated whether recombinant ADAMTS13 (r-ADAMTS13) induces thrombolysis in vivo in mice.