Rena Li

Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease [1]

Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease

Microglia and inflammatory mechanisms in the clearance of amyloid β 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 β peptide (Aβ) forms highly insoluble, β‐pleated aggregates that are widely deposited in the Alzheimers disease (AD) cortex and limbic system. Aggregated Aβ also activates the classical and alternative complement cascades. These properties make Aβ an excellent target for microglial phagocytosis, a view supported by multiple reports, through well established mechanisms of phagocyte clearance. GLIA 40:260–269, 2002.

Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice

The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimers disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.

Estrogen synthesis and signaling pathways during aging: from periphery to brain

Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and brain, and tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. In this article we review tissue and cell-specific estrogen synthesis and estrogen receptor signaling in three parts: (i) synthesis and metabolism, (ii) the distribution of estrogen receptors and signaling, and (iii) estrogen functions and related disorders, including cardiovascular diseases, osteoporosis, Alzheimers disease (AD), and Parkinson disease (PD). This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases.

Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-β 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-β protein (Aβ), a major component of plaques in the Alzheimers 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 κB (NF-κB). Aβ-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-κB 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 Aβ, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Estrogen Enhances Uptake of Amyloid β‐Protein by Microglia Derived from the Human Cortex

Abstract: In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathology of Alzheimers disease (AD). There are two pathological defects in AD: chronic inflammation and impaired clearance of amyloid β‐peptide (Aβ). 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 Aβ 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 Aβ by microglia by quantifying the internalization of aggregated Aβ by human cortical microglia. Aβ uptake was found to be dose‐ and time‐dependent in cultured microglia. Increased Aβ uptake was observed at 1.5 and 24 h after addition of aggregated Aβ (50, 100, or 1,000 nM Aβ), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) β (ER‐β) was also up‐regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of Aβ in cultured microglia. These results indicate that microglia express an ER‐β but that the effect of estrogen on enhancing clearance of Aβ 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.

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

Brain deposits of amyloid beta peptide (Abeta) have been a diagnostic hallmark of Alzheimers 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.

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 Alzheimers disease (AD). In this study, we show that glutamate uptake in astrocytes derived from Alzheimers 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.

Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients.

We reported that tumor necrosis factor receptor I (TNFRI) is required for neuronal death induced by amyloid-beta protein in the Alzheimers disease (AD) brain. However, whether TNF receptor subtypes are expressed and activated differentially in AD brains compared to non-demented brains remains unclear. Our studies on Western blot and ELISA measurements demonstrated that TNFRI levels are increased whereas TNFRII levels are decreased in AD brains compared to non-demented brains (p <0.05). Immunohistochemical results demonstrated that both TNFRI and TNFRII are expressed in neurons in AD and non-demented brains. However, in situ hybridization studies showed little change in the mRNA levels of either type of TNF receptor in the neurons of AD brains compared to non-demented brains. To examine whether different levels of TNF receptors in AD brains are correlated with the alteration of functional binding of TNF receptors, by using 125I-TNF-alpha binding technique, we found that, in AD brains, 125I-TNF-alpha binding affinity to TNFRI is increased, whereas binding affinity to TNFRII is decreased (p < 0.01). These studies reveal a novel observation of abnormal TNF receptor activation in AD brains. Differential TNF receptor protein levels and binding affinities suggest distinct pathogenic mechanisms of neurodegeneration in the AD brain.

CCAAT/enhancer binding protein δ (C/EBPδ) expression and elevation in Alzheimer’s disease

Abstract The CCAAT-enhancer binding protein (C/EBP) family of transcription factors, particularly C/EBPδ, 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-α (TNF-α). These cytokines, in turn, can induce C/EBPδ expression and translocation to the nucleus as an active transcription factor. Because IL-1, IL-6, and TNF-α are increased in pathologically vulnerable regions of the Alzheimer’s disease (AD) brain, we sought to determine if C/EBPδ might be expressed in AD cortex. Immunohistochemistry of AD tissue sections revealed profuse C/EBPδ staining of astrocytes, particularly reactive astrocytes surrounding amyloid β 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/EBPδ in AD compared to ND cortex samples. Additional in vitro studies were pursued in order to characterize functional activity of C/EBPδ in human elderly astrocytes. Consistent with a functionally active transcription factor, C/EBPδ 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/EBPδ-inducing cytokines.