Li-Bang Yang - Academia.edu (original) (raw)

Papers by Li-Bang Yang

Neurobiology of Aging

One of the major pathological hallmarks of Alzheimer's disease (AD) ia the deposition of P-amyloi... more One of the major pathological hallmarks of Alzheimer's disease (AD) ia the deposition of P-amyloid (AP) in senile plaques (SP). Recently, it has been proposed that the product of a new candidate gene, called apolipoprotein D (apoD), is involved in AD neurodegeneration. However, no direct evidence has yet been provided about mvolvement of apoD in the pathogeneais of AD. We investigated the distribution of apoD immunoreactivity in non-demented control patients, AD cases, AD ca\es with diffuse Lewy bodies (ADIDLB). pure Lewy body (LB) and Pick's disease (PD). In control cases, apoD immunoreactivity was restricted to a subset of neuronal and glial cells, and occasional blood vessels. In addition, AD and AD/DLB cases showed apoD deposits with morphological characteristics of SP. There plaque-like deposits of apoD immunoreactivily

Proceedings of the National Academy of Sciences

Whether elevated ␤-secretase (BACE) activity is related to plaque formation or amyloid ␤ peptide ... more Whether elevated ␤-secretase (BACE) activity is related to plaque formation or amyloid ␤ peptide (A␤) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various A␤ species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the A␤ species detected in rapidly autopsied brains (<3 h) with sporadic AD were A␤ 1-x and A␤ 1-42, as well as A␤x-42. To establish a linkage between A␤ 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 A␤ 1-x and A␤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 A␤ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased A␤ production and enhanced deposition of amyloid plaques in sporadic AD patients.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2000

Complement defense 59 (CD59) is a cell surface glycophosphoinositol (GPI)-anchored protein that p... more Complement defense 59 (CD59) is a cell surface glycophosphoinositol (GPI)-anchored protein that prevents complement membrane attack complex (MAC) assembly. Here, we present evidence from ELISA assays that CD59 protein levels are significantly decreased in the frontal cortex and hippocampus of Alzheimer's disease (AD) compared with nondemented elderly (ND) patients, whereas complement component 9, a final component to form MAC, is significantly increased. To further confirm the CD59 deficit, PI-specific phospholipase C (PIPLC) was used to cleave the CD59 GPI anchor at the cell surface in intact slices from AD and ND cortex. CD59 released by PIPLC cleavage was significantly reduced in AD compared with ND samples. By the use of a ribonuclease protection technique, amyloid beta-peptide was found to downregulate CD59 expression at the mRNA level, suggesting a partial explanation of CD59 deficits in the AD brain. To evaluate the pathophysiological significance of CD59 alterations in n...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2002

Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, b... more 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 re...

Science (New York, N.Y.), Jan 26, 1984

Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids a... more Adriamycin (doxorubicin), a potent antitumor drug in clinical use, interacts with nucleic acids and cell membranes, but the molecular basis for its antitumor activity is unknown. Similar to a number of intercalative antitumor drugs and nonintercalative epipodophyllotoxins (VP-16 and VM-26), adriamycin has been shown to induce single- and double-strand breaks in DNA. These strand breaks are unusual because a covalently bound protein appears to be associated with each broken phosphodiester bond. In studies in vitro, mammalian DNA topoisomerase II mediates DNA damage by adriamycin and other related antitumor drugs.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 24, 2014

We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheim... more We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons). The exogenous introduction of GFRα1, but not of its binding partner α1-neural cell adhesion molecule, or RET into AD neurons restored the effect of GDNF on neuronal survival. Moreover, between NC and AD neurons, the AMPA receptor blocker CNQX and the NMDA receptor blocker AP-5 had op...

Journal of Neuroscience, 2004

Our studies suggest a novel neuronal response of A␤, which occurs through a TNF receptor signalin... more Our studies suggest a novel neuronal response of A␤, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Proceedings of the National Academy of Sciences, 2004

Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta pe... more Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;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 (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Neuroscience Letters, 2001

Brain in¯ammation is widely documented to occur in Alzheimer's disease (AD), but its sources are ... more Brain in¯ammation is widely documented to occur in Alzheimer's disease (AD), but its sources are still incompletely understood. Here, we present in vitro and in situ evidence that, like amyloid b peptide (Ab), tau, the major protein constituent of the neuro®brillary tangle, is a potent, antibody-independent activator of the classical complement pathway. Complement activation, in turn, is known to drive numerous in¯ammatory responses, including scavenger cell activation and cytokine production. Because Ab deposits and extracellular tangles are present from early preclinical to terminal stages of AD, their ability to activate complement provides a ready mechanism for initiating and sustaining chronic, low-level in¯ammatory responses that may cumulate over the disease course. q

Neurobiology of Aging, 2000

Poster Pre.rentation: Molecular and Cellular Biology IV s255 mediator of cellular processes and a... more Poster Pre.rentation: Molecular and Cellular Biology IV s255 mediator of cellular processes and a major component of the constitutive immune response. We have previously shown that the enhancement of macrophage NO production is isoform specific with APOE4<APOE3. One potentxd site for modulation of NO production is the uptake of arginine, the substrate for nitric oxide synthase (NOS). Arginine tranrport is camed out by Na'-independent cationic transporterr (formerly known as y+ transporters) whose expression is tightly coupled to NOS expression. Usmg 'H+-arginine. we examined arginine uptake in microglia and neurons cultured from wild-type. APOE knockout mtce and mice made transgenic for the human APOE 3 or 4 allele on a mouse APOE knockout background. For micro&, the cells were pretreated with y-interferon (IFN) for 8 hours in IO or 100 FM arginine, washed and then treated for 4 hours with the double-stranded polyribonucleotide, Polyinosinic:Polycytidylic (PIG). or lipopolyaaccharide (LPS) followed by determinatton of arginine uptake. Neuron\ were not pretreated with $FN. Arginine transport was measured at physiological level\ of @nine and wa\ blocked by Gmultaneow treatment with N-monomethyl arginine (NMMA). Both PIC and LPS sigmficantly increased arginine transport compared to untreated conditions in microglia while PIC increased transport in neurons. Microglia and neurons from APOE 4 transgenic mace demonstrated a significantly higher level of arginine uptake

Journal of Neurochemistry, 2002

In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in... more In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathology of Alzheimer's disease (AD). There are two pathological defects in AD: chronic inflammation and impaired clearance of amyloid ␤-peptide (A␤). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear A␤ deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to determine the relationship between estrogen treatment and internalization of A␤ by microglia by quantifying the internalization of aggregated A␤ by human cortical microglia. A␤ uptake was found to be dose-and time-dependent in cultured microglia. Increased A␤ uptake was observed at 1.5 and 24 h after addition of aggregated A␤ (50, 100, or 1,000 nM A␤), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) ␤ (ER-␤) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of A␤ in cultured microglia. These results indicate that microglia express an ER-␤ but that the effect of estrogen on enhancing clearance of A␤ may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.

Glia, 2001

We have previously developed and characterized isolated microglia and astrocyte cultures from rap... more We have previously developed and characterized isolated microglia and astrocyte cultures from rapid (Ͻ4 h) brain autopsies of Alzheimer's disease (AD) and nondemented elderly control (ND) patients. In the present study, we evaluate the inflammatory repertoire of AD and ND microglia cultured from white matter (corpus callosum) and gray matter (superior frontal gyrus) with respect to three major proinflammatory cytokines, three chemokines, a classical pathway complement component, a scavenger cell growth factor, and a reactive nitrogen intermediate. Significant, dosedependent increases in the production of pro-interleukin-1␤ (pro-IL-1␤), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide-1␣ (MIP-1␣), IL-8, and macrophage colony-stimulating factor (M-CSF) were observed after exposure to pre-aggregated amyloid ␤ peptide (1-42) (A␤1-42). Across constitutive and A␤-stimulated conditions, secretion of complement component C1q, a reactive nitrogen intermediate, and M-CSF was significantly higher in AD compared with ND microglia. Taken together with previous in situ hybridization findings, these results demonstrate unequivocally that elderly human microglia provide a brain endogenous source for a wide range of inflammatory mediators.GLIA 35: 72-79, 2001.

The American Journal of Pathology, 2002

Isolation and culture of mature neurons from affected brain regions during diseased states provid... more Isolation and culture of mature neurons from affected brain regions during diseased states provide a wellsuited 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 ␥-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.