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Biomedical subjects

Rena Li

Publications and source records attributed to Rena Li.

13 recordsLinked to original sources
PubMed2005

Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model.

Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased beta amyloid peptide (Abeta) deposition. These mice also exhibited increased Abeta production, and microglia cultures prepared from the brains of these mice were impaired in Abeta clearance/degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.

Amyloid Precursor Protein Secretases↗
PubMed2005

Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes.

Brain deposits of amyloid beta peptide (Abeta) have been a diagnostic hallmark of Alzheimer's disease (AD) for nearly a century. Recent studies have demonstrated that Abeta is also present in peripheral blood. Here, we present evidence that circulating Abeta42 is subject to complement C3b-dependent adherence to complement receptor 1 (CR1) on erythrocytes, a classical set of mechanisms by which pathogens and proteins recognized as foreign are cleared from the bloodstream. Levels of Abeta42 targeted by this pathway differ significantly in AD compared to mild cognitive impairment and nondemented elderly controls.

Alzheimer Disease↗
PubMed2005

Estrogen and brain: synthesis, function and diseases.

This review summaries recent evidence from clinical and basic science studies on estrogen central nervous system. For decades, estrogen was thought of only as a "sex hormone" and plays a fundamental role in regulating behavioral and physiological events. In recent years, accumulated evidence shows that estrogen also plays very important roles in the brain. Recent basic science studies show that estrogen treatment decreases the neuronal response to various forms of insult through the regulation of both estrogen synthesis and estrogen receptor expression in the brain. Some clinical evidence also suggests that estrogen deprivation might be implicated as a risk factor in various neurodegenerative diseases. Estrogen may play a neuroprotective role through estrogen dependent alterations in cell survival, enhancement of synaptic transmission and neurogenesis. Some of the mechanisms underlying these effects are independent of the classical nuclear estrogen receptors and involve direct modulation of neurotransmitter receptor function, or anti-oxidant activities of estrogen. It is controversial whether estrogen is indicated in the prevention or treatment of various brain disorders such as Alzheimer's disease. The conflicting findings suggest that several variables, including age, estrogen dose and formulation, the length of treatment, may determine whether the potential benefits of estrogen treatment would outweigh the associated risks.

Alzheimer Disease↗
PubMed2004

Deficiency of the Mre11 DNA repair complex in Alzheimer's disease brains.

The hallmarks of Alzheimer's disease (AD) brains are deposition of Abeta plaques, appearance of neurofibrillary tangles, and extensive loss of neuronal cells. While Abeta plaques and neurofibrillary tangles play a significant role in the pathogenic dysfunction of neurons, factors that accelerate the neurodegenerating process remain to be defined. One set of factors examined in this study is the Mre11 protein complex, composed of Rad50, Mre11 and Nbs1. This protein complex plays an essential role in cellular responses to DNA damage, such as initiating cell cycle checkpoints and repairing damaged DNA. A defect in any component of this protein complex is detrimental to cells. Recently, several groups have observed abnormal cell cycle regulation and/or accumulated DNA damage in AD neurons. These pathological alterations could conceivably be caused or exacerbated by any compromise in the Mre11 complex. In this study, we compared the levels of the Mre11 complex proteins in brain samples from AD and age-matched non-dementia controls. We show for the first time that the Mre11 complex proteins are present in neurons of the adult human cortex and cerebellum. These proteins were found substantially reduced in the neurons of AD cortex. Our finding suggests that the loss of the Mre11 complex may be associated with the pathogenesis of AD.

Acid Anhydride Hydrolases↗
PubMed2004

Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients.

Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Abeta species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Abeta species detected in rapidly autopsied brains (<3 h) with sporadic AD were Abeta(1-x) and Abeta(1-42), as well as Abeta(x-42). To establish a linkage between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Abeta(1-x) and Abeta(1-42) production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Abeta loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Abeta production and enhanced deposition of amyloid plaques in sporadic AD patients.

Alzheimer Disease↗
PubMed2004

Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death.

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-beta protein (Abeta), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor kappaB (NF-kappaB). Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-kappaB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Abeta, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Active Transport, Cell Nucleus↗
PubMed2004

CCAAT/enhancer binding protein delta (C/EBPdelta) expression and elevation in Alzheimer's disease.

The CCAAT-enhancer binding protein (C/EBP) family of transcription factors, particularly C/EBPdelta, is well known to regulate or co-regulate a wide range of inflammatory mediators and mechanisms in the periphery, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). These cytokines, in turn, can induce C/EBPdelta expression and translocation to the nucleus as an active transcription factor. Because IL-1, IL-6, and TNF-alpha are increased in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, we sought to determine if C/EBPdelta might be expressed in AD cortex. Immunohistochemistry of AD tissue sections revealed profuse C/EBPdelta staining of astrocytes, particularly reactive astrocytes surrounding amyloid beta peptide deposits. Substantially less immunoreactivity was observed in comparable sections from nondemented elderly control (ND) patients. These qualitative findings were consistent with quantitative Western blot densitometry results showing significant increases in C/EBPdelta in AD compared to ND cortex samples. Additional in vitro studies were pursued in order to characterize functional activity of C/EBPdelta in human elderly astrocytes. Consistent with a functionally active transcription factor, C/EBPdelta immunoreactivity predominated in the nucleus of cultured AD and ND astrocytes, and exhibited increases and nuclear localization, as determined by Western blots and electrophoretic mobility shifts after exposure to C/EBPdelta-inducing cytokines.

Active Transport, Cell Nucleus↗
PubMed2004

Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid.

BACKGROUND: While the pathogenesis of manic-depressive, or bipolar, illness is unknown, an excess of intracellular sodium and calcium concentrations is thought to contribute to the development of the illness. Previous work has demonstrated a reduced adaptive response of the sodium pump to ethacrynic acid in lymphocytes obtained from bipolar subjects compared to psychiatrically normal controls. METHODS: To further examine this phenomenon, we investigated several aspects of sodium pump response (transcription, translation, activity, and intracellular ion concentration) in lymphoblastoid cell lines derived from bipolar subjects and matched normal controls. Cells were treated with ethacrynic acid 100 microM for 3 days. RESULTS: Normal control-derived cells exhibited an upregulation of sodium pump mRNA synthesis, protein expression, pump-specific binding and activity, and were able to maintain a normal intracellular sodium concentration. Cells derived from bipolar individuals did not alter sodium pump parameters in any way, and consequently, had a higher intracellular sodium concentration. LIMITATIONS: While bipolar lymphoblasts were from an inbred Old Order Amish population, the normal controls were from an outbred population. CONCLUSIONS: The results suggest that bipolar illness is associated with an abnormality in cellular sodium homeostatic regulation.

Adult↗
PubMed2002

Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways.

Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, but their roles in the brain remain unclear. Here we present a novel interaction between TNFR subtypes and TNF-alpha in the brain. Our studies on target-depleted TNFR in mice show that TNF-alpha has little effect on hippocampal neurons in which TNFRI, containing an "intracellular death domain," is absent (TNFRI -/-), whereas neurons from TNFRII knock-out mice are vulnerable to TNF-alpha even at low doses. Moreover, little nuclear factor-kappaB (NF-kappaB) translocation is induced by TNF-alpha in neurons of TNFRI -/-, whereas NF-kappaB subunit p65 is still translocated from the cytoplasm into the nucleus in neurons from wild-type and TNFRII -/- mice. Furthermore, p38 mitogen-activated protein (MAP) kinase activity is upregulated in neurons from both wild-type and TNFRI -/-, but no alteration of p38 MAP kinase was found in neurons from TNFRII. Results from overexpression of TNF receptors further support the above findings. NT2 neuronal-like cells transiently transfected with TNFRI are very sensitive to TNF-alpha, whereas TNF-alpha is not toxic and even seems to be trophic to the cells with TNFRII overexpression. Last, our radioligand-binding experiments demonstrate that TNF-alpha binds TNFRI with high affinity (K(d) of 0.6 nm), whereas TNFRII shows lower binding affinity (K(d) of 1.14 nm) to TNF-alpha in NT2 transfected cells. Together, these studies reveal novel neuronal responses of TNF-alpha in mediating consequences of TNF receptor activation differently. Subsequent neuronal death or survival may ultimately depend on a particular subtype of TNF receptor that is predominately expressed in neurons of the brain during neural development or with neurological diseases.

Active Transport, Cell Nucleus↗
PubMed2002

Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide.

There is now abundant evidence that brain microglia, when activated, have the lineage, receptors, and synthetic capacity to participate in both potentially neurotoxic inflammatory responses and potentially beneficial phagocytic responses. Amyloid beta peptide (Abeta) forms highly insoluble, beta-pleated aggregates that are widely deposited in the Alzheimer's disease (AD) cortex and limbic system. Aggregated Abeta also activates the classical and alternative complement cascades. These properties make Abeta an excellent target for microglial phagocytosis, a view supported by multiple reports, through well established mechanisms of phagocyte clearance.

Alzheimer Disease↗
PubMed2002

Isolation of living neurons from human elderly brains using the immunomagnetic sorting DNA-linker system.

Isolation and culture of mature neurons from affected brain regions during diseased states provide a well-suited in vitro model system to study age-related neurodegeneration under dynamic conditions at cellular levels. We have developed a novel technique to isolate living neurons from rapidly autopsied human elderly brains, and have succeeded in keeping them alive in vitro. Specifically, the parietal cortex blocks were fractionated by density gradients and further enriched for neurons by an immunomagnetic sorting DNA-linker technique. The postmortem interval averaged 2.6 hours. After isolation and purification of neurons using this technology, the cells were maintained in vitro for 2 weeks. Our evaluation revealed that 80% of the isolated cells were neurons and they exhibited neurotransmitter phenotypes (glutamate and gamma-aminobutyric acid) as well as glutamate receptors. Studies on cell viability and calcium influx suggest that these isolated living cortical neurons still retain their typical neuronal functions. Our present study demonstrates that neurons isolated from human elderly brain autopsies can survive in vitro and maintain their functional properties. Our study has opened an opportunity to apply such neurons to dynamic pharmacological studies of neurological disorders at the single-cell level.

Aged↗
PubMed2002

Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients.

Estrogen is thought to play a protective role against neurodegeneration through a variety of mechanisms including the activation of growth factors, the control of synaptic plasticity, and the reduction of response to various insults, such as iron and glutamate. Increasing evidence indicates an increased level of extracellular glutamate and a down-regulation of glutamate transporters in Alzheimer's disease (AD). In this study, we show that glutamate uptake in astrocytes derived from Alzheimer's patients is significantly lower than that from non-demented controls. Estrogen treatment increases glutamate uptake in a dose-dependent pattern. Two glutamate transporters, GLT-1 and GLAST, are expressed in the astrocytes. Up-regulation of the glutamate transporters is induced by estrogen treatment in AD astrocytes only. Our data suggest that the action of estrogen on glutamate uptake by astrocytes might contribute to its potential neuroprotective role in AD.

Alzheimer Disease↗