Towards the Integrative Theory of Alzheimer's Disease: Linking Molecular Mechanisms of Neurotoxicity, Beta-amyloid Biomarkers, and the Diagnosis.

Introduction: A major gap in amyloid-centric theories of Alzheimer's disease (AD) is that even though amyloid fibrils per se are not toxic in vitro, the diagnosis of AD clearly correlates with the density of beta-amyloid (Aβ) deposits. Based on our proposed amyloid degradation toxicity hypothesis, we developed a mathematical model explaining this discrepancy. It suggests that cytotoxicity depends on the cellular uptake of soluble Aβ rather than on the presence of amyloid aggregates.

Discovery and Preclinical Development of Novel Intraocular Pressure-Lowering Rho Kinase Inhibitor: Corticosteroid Conjugates.

A new class of ocular steroids designed to mitigate steroid-induced intraocular pressure (IOP) elevation while maintaining anti-inflammatory activity was developed. Herein is described the discovery and preclinical characterization of ROCK'Ster compound . Codrugs consisting of a Rho kinase inhibitor (ROCKi) and a corticosteroid were synthesized.

Patients with Alzheimer's disease have an increased removal rate of soluble beta-amyloid-42.

Senile plaques, which are mostly composed of beta-amyloid peptide, are the main signature of Alzheimer's disease (AD). Two main forms of beta-amyloid in humans are 40 and 42-amino acid, long; the latter is considered more relevant to AD etiology. The concentration of soluble beta-amyloid-42 (Aβ42) in cerebrospinal fluid (CSF-Aβ42) and the density of amyloid depositions have a strong negative correlation.

Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid.

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people. Neuronal death in AD is initiated by oligomeric amyloid-β (Aβ) peptides. Recently, we proposed the amyloid degradation toxicity hypothesis, which explains multiple major observations associated with AD including autophagy failure and a decreased metabolism.

Intracellular ion changes induced by the exposure to beta-amyloid can be explained by the formation of channels in the lysosomal membranes.

In this manuscript, we reassess the data on beta-amyloid-induced changes of intracellular ions concentrations published previously by Abramov et al. (2003, 2004). Their observations made using high-resolution confocal microscopy with fast temporal resolution of images formed by fluorescent ion-sensitive fluorescent probes in living cells represent an unequivocal support for the amyloid channel theory.

Mini-review: Amyloid degradation toxicity hypothesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people. Neuronal death in AD is initiated by oligomeric amyloid-β (Aβ) peptides. The amyloid channel hypothesis readily explains the primary molecular damage but does not address major observations associated with AD such as autophagy failure and decreased metabolism.

Degradation Products of Amyloid Protein: Are They The Culprits?

Objectives: Beta-amyloid (Aβ) peptides are most toxic to cells in oligomeric form. It is commonly accepted that oligomers can form ion channels in cell membranes and allow calcium and other ions to enter cells. The activation of other mechanisms, such as apoptosis or lipid peroxidation, aggravates the toxicity, but it itself can result from the same initial point, that is, ion disturbance due to an increased permeability of membranes.

Flow cytometry method to quantify the formation of beta-amyloid membrane ion channels.

It is accepted that the cytotoxicity of beta-amyloid is mediated by its oligomers. Amyloid peptides can form ion channels in cell membranes and allow calcium and other ions to enter cells. In this project, we developed a technique to quantify the appearance of calcium in liposomes and applied this technique to study the effect of amyloid peptides on the permeability of membranes.

Automatic analysis of treadmill running to estimate times to fatigue and exhaustion in rodents.

Introduction: The determination of fatigue and exhaustion in experimental animals is complicated by the subjective nature of the measurement. Typically, it requires an observer to watch exercising animals, e.g.

Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3C: Implications for brain, brown adipose tissue, and muscle physiology.

Tissue temperature increases, when oxidative metabolism is boosted. The source of nutrients and oxygen for this metabolism is the blood. The blood also cools down the tissue, and this is the only cooling mechanism, when direct dissipation of heat from the tissue to the environment is insignificant, , in the brain.

Disinhibiting neurons in the dorsomedial hypothalamus delays the onset of exertional fatigue and exhaustion in rats exercising in a warm environment.

Stimulants cause hyperthermia, in part, by increasing heat generation through exercise. Stimulants also delay the onset of fatigue and exhaustion allowing animals to exercise longer. If used in a warm environment, this combination (increased exercise and decreased fatigue) can cause heat stroke.

Circadian variability of body temperature responses to methamphetamine.

Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine.

The non-peptide CRH1-antagonist CP-154,526 elicits a paradoxical route-dependent activation of the HPA axis.

The corticotropin-releasing hormone (CRH) plays an important role in mediating physiological response to stress and is thought to be involved in the development of various psychiatric disorders. In this paper, we compare the differences between the effect of intraperitoneal (i.p.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively.

Amphetamine enhances endurance by increasing heat dissipation.

Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine-trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline).

Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats.

In freely behaving rats, variations in heart rate (HR) and blood pressure (BP) are coupled closely with changes in locomotor activity (Act). We have attempted to characterize this relationship mathematically. In 10- and 16-week-old rats, HR, BP and Act were recorded telemetrically every minute for 2 days under 12h:12h light-dark cycling.

Exercise activates compensatory thermoregulatory reaction in rats: a modeling study.

The importance of exercise is increasingly emphasized for maintaining health. However, exercise itself can pose threats to health such as the development of exertional heat shock in warm environments. Therefore, it is important to understand how the thermoregulation system adjusts during exercise and how alterations of this can contribute to heat stroke.

Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1 mg/kg.

Yohimbine is a prototypical alpha2-adrenergic receptor antagonist. Due to its relatively high selectivity, yohimbine is often used in experiments whose purpose is to examine the role of these receptors. For example, yohimbine has been employed at doses of 1-5 mg/kg to reinstate drug-seeking behavior after extinction or to antagonize general anesthesia, an effects presumably being a consequence of blocking alpha2-adrenergic receptors.

Orexinergic neurotransmission in temperature responses to methamphetamine and stress: mathematical modeling as a data assimilation approach.

Experimental Data: Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t > 60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress.

Treadmill running restores MDMA-mediated hyperthermia prevented by inhibition of the dorsomedial hypothalamus.

The contribution of exercise to hyperthermia mediated by MDMA is not known. We recently showed that inhibiting the dorsomedial hypothalamus (DMH) attenuated spontaneous locomotion and hyperthermia and prevented deaths in rats given MDMA in a warm environment. The goal of this study was to confirm that restoring locomotion through a treadmill would reverse these effects thereby confirming that locomotion mediated by the DMH contributes to MDMA-mediated hyperthermia.

Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment.

The central mechanisms through which MDMA mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA.

Meth math: modeling temperature responses to methamphetamine.

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN).

The Ergogenic Effect of Amphetamine.

Amphetamine (Amp) increases exercise duration. It is thought to do so by masking fatigue, but there have been very few studies looking at the effect of amphetamine on VO and running economy. Furthermore, it is unknown if amphetamine's effect on exercise duration occurs in a warm environment.

Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA.

Acute and chronic complications from the substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) are linked to activation of the hypothalamic-pituitary-adrenal (HPA) axis. How MDMA activates the HPA axis is not known. HPA responses to stress are known to be mediated through the paraventricular (PVH) hypothalamus and to involve serotonin-1a (5-HT1A) receptors.

Contribution of infralimbic cortex in the cardiovascular response to acute stress.

The infralimbic region of the medial prefrontal cortex (IL) modulates autonomic and neuroendocrine function via projections to subcortical structures involved in the response to stress. We evaluated the contribution of the IL to the cardiovascular response evoked by acute stress. Under anesthesia (80 mg/kg ketamine-11.