Neurochemical changes following a single dose of polybrominated diphenyl ether 47 in mice.

Polybrominated diphenyl ethers (PBDEs) are commonly used as commercial flame retardants in a variety of products, including plastics and textiles. Previous studies in our laboratory, and in the literature, showed that exposure to a specific PBDE congener (PBDE 47) during a critical period of brain development may lead to developmental delays and hyperactivity in adulthood. To date, the underlying causes of these behavioral alterations are unknown, although in vitro studies linked PBDEs with potential alterations in neurotransmitter levels, particularly acetylcholine (ACh) and dopamine (DA).

Lack of alterations in thyroid hormones following exposure to polybrominated diphenyl ether 47 during a period of rapid brain development in mice.

Thyroid alterations have been shown to occur following exposure to polybrominated diphenyl ether (PBDE) mixtures, possibly indicating that disruptions in thyroid hormone levels may underlie behavior deficits observed in animals following postnatal PBDE exposure. This study determined whether acute postnatal exposure to PBDE-47 would alter thyroid hormones. Mice were dosed with PBDE-47 on postnatal day 10, and serum collected either 1, 5, or 10 days after the dose.

Protein oxidation and cellular homeostasis: Emphasis on metabolism.

Reactive oxygen species (ROS) are generated as the result of a number of physiological and pathological processes. Once formed ROS can promote multiple forms of oxidative damage, including protein oxidation, and thereby influence the function of a diverse array of cellular processes. This review summarizes the mechanisms by which ROS are generated in a variety of cell types, outlines the mechanisms which control the levels of ROS, and describes specific proteins which are common targets of ROS.

Age-related alterations of Apolipoprotein E and interleukin-1beta in the aging brain.

With normal aging, the brain undergoes several alterations including reduced neuronal functioning and alterations in glia homeostasis. An increase in inflammatory signaling has also been reported in some studies of the aging brain, with inflammation potentially mediating age-related changes in the brain. Apolipoprotein E (ApoE) is produced in the brain and has been shown to possess anti-inflammatory properties in a variety of paradigms.

Modulation of apolipoprotein E and interleukin-1beta in the aging liver.

With aging there is a decline in liver function that includes reductions in hepatic blood flow, metabolite clearance, and impaired tissue repair following injury. An increase in inflammatory signaling is often observed during aging, with inflammation potentially mediating age-related changes in the liver. Apolipoprotein E (ApoE) is primarily produced by the liver and has been shown to possess anti-inflammatory properties in a variety of paradigms and experimental settings.

Astrocytes: regulation of brain homeostasis via apolipoprotein E.

Astrocytes are derived from the ventricular and subventricular zones of the neural plate, though there is controversy over their derivation from astrocyte-specific precursor cells or radial glia intermediates. Astrocytes are the most abundant cell type in the brain and contribute to brain homeostasis in several ways, including buffering of extracellular K+, regulating neurotransmitter release, forming the blood-brain barrier (BBB), releasing growth factors, and regulating the brain immune response. In addition, astrocytes have been shown to release apolipoprotein E (ApoE), which has been shown to regulate neurotransmission, growth factor release, and immune responses.

Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain.

In order to successfully respond to stress all cells rely on the ability of the proteasomal and lysosomal proteolytic pathways to continually maintain protein turnover. Increasing evidence suggests that as part of normal aging there are age-related impairments in protein turnover by the proteasomal proteolytic pathway, and perturbations of the lysosomal proteolytic pathway. Furthermore, with numerous studies suggest an elevated level of a specialized form of lysosomal proteolysis (autophagy or macroautophagy) occurs during the aging of multiple cell types.

Loss of an individual proteasome subunit alters motor function but not cognitive function or ambulation in mice.

The proteasome is a large intracellular protease, composed of multiple subunits, that is present in all cells. In the present study we examined motor function, cognitive function, and ambulation in transgenic mice that lack the low molecular protein 2 (LMP2) proteasome subunit. Comparison of LMP2 knock out (LMP2 KO) mice and non-transgenic mice of the same background demonstrate that LMP2 KO mice exhibit a higher degree of motor function, but possess a similar level of cognitive function and ambulation, as compared to non-transgenic control mice.

Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain.

Neurodegeneration, synaptic alterations, and gliosis are prominent features of human immunodeficiency virus (HIV) encephalitis, but HIV encephalitis is distinct from other viral encephalitides because neurodegeneration occurs in uninfected neurons at anatomical sites that are often distant from the site of viral replication. The HIV protein Tat is both neurotoxic and proinflammatory; however, its contribution to HIV-related synaptic dysfunction remains unknown. To determine the consequences of continuous Tat production in brain, we genetically engineered rat C6 glioma cells to stably produce Tat and stereotaxically infused these cells into the rat striatum or hippocampus.

The proteasome in brain aging.

The proteasome is a large intracellular protease, present in all cells of the central nervous system (CNS), that is responsible for the majority of intracellular protein degradation. In particular, the proteasome is responsible for the degradation of most oxidized, aggregated, and misfolded proteins. The importance of proteasome activity to neuronal homeostasis is highlighted by previous studies demonstrating that proteasome inhibition alone is sufficient to induce neuron death in vitro.

Analysis of Werner's expression within the brain and primary neuronal culture.

Werner's syndrome is a genetic progeria disorder caused by mutation of the Werner gene (WRN). The presence of mutations in the WRN gene is believed to result in a deleterious loss of normal WRN function, which has been best characterized for its role as a DNA helicase and exonuclease. The WRN gene is known to be expressed within the central nervous system, with Werner's syndrome associated with several neuropathological abnormalities including brain atrophy, gliosis and extensive cytoskeletal abnormalities.