Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in beef and dairy products. CLA has been reported to reduce body fat. To examine the mechanism(s) of CLA reduction of fat mass, female C57BL/6J mice were fed standard semipurified diets (10% fat of total energy) with or without CLA (1% wt/wt). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling (TUNEL) and DNA fragmentation analysis revealed that fat-mass decrease by CLA was mainly due to apoptosis. Tumor necrosis factor (TNF)-␣ and uncoupling protein (UCP)-2 mRNA levels increased 12-and 6-fold, respectively, in isolated adipocytes from CLA-fed mice compared with control mice. Because it is known that TNF-␣ induces apoptosis of adipocytes and upregulates UCP2 mRNA, a marked increase of TNF-␣ mRNA with an increase of UCP2 in adipocytes caused CLA-induced apoptosis. However, with a decrease of fat mass, CLA supplementation resulted in a state resembling lipoatrophic diabetes: ablation of brown adipose tissue, a marked reduction of white adipose tissue, marked hepatomegaly, and marked insulin resistance. CLA supplementation decreased blood leptin levels, but continuous leptin infusion reversed hyperinsulinemia, indicating that leptin depletion contributes to the development of insulin resistance. These results demonstrate that intake of CLA reduces adipose tissue by apoptosis and results in lipodystrophy, but hyperinsulinemia by CLA can be normalized by leptin administration. Diabetes 49:1534-1542, 2000 C onjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. The major dietary sources of CLA for humans are beef and dairy products (1). There is a great interest in CLA because of its anticarcinogenic and antiatherogenic properties and its ability to reduce body fat while enhancing lean body mass (2). Reduction of body fats by CLA was observed in pigs (3), mice (4,5), and hamsters (6).In this study, we investigated the mechanism(s) of CLAmediated reduction of fat mass in mice. Reduction of fat mass by CLA was due to apoptosis. Initially, we expected the beneficial effect of CLA-induced fat mass decrease, such as improvement of insulin resistance and reduction of blood triglyceride concentration. Unexpectedly, however, rapid reduction of fat mass by CLA resulted in marked insulin resistance and hepatomegaly. These metabolic abnormalities are characteristics of lipodystrophy (7,8). During this study, Delany et al. (9) also reported that CLA reduced body fat but resulted in hyperinsulinemia and liver enlargement in AKR/J male mice. To understand the mechanism(s) of CLAinduced lipodystrophy, we examined expression levels of several genes important in energy expenditure and lipid and carbohydrate metabolism in adipose tissues and isolated adipocytes. Furthermore, effects of leptin infusion on CLAinduced insulin resistance were also examined. RESEARCH DESIGN AND METHODSExperimental protocols. Female C57BL/6J mice were obt...
Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, includingParkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., ␣-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by -amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)70͞90 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.
Amyloid- protein (A) aggregates in the brain to form senile plaques. By using thioflavin T, a dye that specifically binds to fibrillar structures, we found that metals such as Zn(II) and Cu(II) normally inhibit amyloid -aggregation. Another method for detecting A, which does not distinguish the types of aggregates, showed that these metals induce a non--sheeted aggregation, as reported previously. Secondary structural analysis and microscopic studies revealed that metals induced A to make non-fibrillar aggregates by disrupting -sheet formation. These non-fibrillar A aggregates displayed much weaker Congo Red birefringence, and in separate cell culture experiments, were less toxic than self -aggregates, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The toxicity of soluble A was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of A in generating oxidative stress. Finally, under an acidic condition, similar to that in the inflammation associated with senile plaques, -aggregation was robustly facilitated at one specific concentration of Zn(II) in the presence of heparin. However, because a higher concentration of Zn(II) virtually abolished this abnormal phenomenon, and at normal pH any concentrations strongly inhibit -aggregation and its associated cytotoxicity, including its anti-oxidative nature we suggest that Zn(II) has an overall protective effect against -amyloid toxicity. Amyloid- protein (A)1 is one of the main components of senile plaques, a pathological hallmark of Alzheimer's disease (AD) (1, 2). Although A is undisputedly associated with the pathology of AD, it is still an open question as to what specific aspects of A and its processing are the important variables in the pathophysiology of the disease. For example, fibrillar A, but not non-amyloidogenic, amorphous aggregates of A, was reported to cause neuronal cell death in primary rat hippocampal cultures (3), and soluble monomeric species of A are relatively nontoxic as compared with fibrillar A (4). Thus, these in vitro studies suggest that the degree of -aggregation is particularly important for neurotoxicity to occur (5-8). However, many controversial results from in vivo studies have been reported concerning the pathological role of plaque formation in AD. Irizarry et al. (9) reported that transgenic (TG) mice expressing human A failed to exhibit neuronal loss despite depositing substantial amounts of A. On the other hand, TG mice that express Swedish mutant amyloid precursor protein (APP) formed plaques that were detected by both an anti-APP antibody and a -sheet specific dye (10). Moreover, these APP TG mice also displayed memory deficits. Taken together, these results indicate that, although the plaque assembly process may require further investigation, amyloid -aggregation certainly is an essential event in the pathogenesis of AD.Based on these lines of evidence, the search for a compound that interrupts -aggregation and thus protects agai...
Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein.Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.
The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease. Expression of modest levels of the longest human tau isoform with this mutation under the control of the ␣-calcium-calmodulindependent kinase-II promoter in transgenic (Tg) mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wild-type tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Straight tau filaments were recovered from Sarkosyl-insoluble fractions from only the aged Tg brains. Behaviorally, aged Tg mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice that exhibit a phenotype mimicking R406W FTDP-17 provide an animal model for investigating the adverse properties associated with this mutation, which might potentially recapitulate some etiological events in Alzheimer's disease.
A clear understanding of cell fate regulation during differentiation is key in successfully using stem cells for therapeutic applications. Here, we report that mild electrical stimulation strongly influences embryonic stem cells to assume a neuronal fate. Although the resulting neuronal cells showed no sign of specific terminal differentiation in culture, they showed potential to differentiate into various types of neurons in vivo, and, in adult mice, contributed to the injured spinal cord as neuronal cells. Induction of calcium ion influx is significant in this differentiation system. This phenomenon opens up possibilities for understanding novel mechanisms underlying cellular differentiation and early development, and, perhaps more importantly, suggests possibilities for treatments in medical contexts.
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