Interleukin‐1β dissociates β‐amyloid precursor protein and β‐amyloid peptide secretion

Vasilakos, John P.; Carroll, Richard T.; Emmerling, Mark R.; Doyle, P; Davis, Robert E.; Kim, K.S.; Shivers, Brenda D.

doi:10.1016/0014-5793(94)01142-7

Cited by 33 publications

(16 citation statements)

References 21 publications

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“…The secretory processes of s␤APP and A␤ were also differentially affected by interleukin-1␤ stimulation (42). Thus, in certain cell systems s␤APP secretion and A␤ generation apparently are not mutually exclusive.…”

Section: Mutations That Inhibit Binding Of X11 To the Yenpty Motif Ofmentioning

confidence: 82%

X11 Interaction with β-Amyloid Precursor Protein Modulates Its Cellular Stabilization and Reduces Amyloid β-Protein Secretion

Sastre¹,

Turner²,

Levy³

1998

Journal of Biological Chemistry

131

115

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The protein interaction domain of the neuronal protein X11 binds to the YENPTY motif within the cytoplasmic domain of ␤-amyloid precursor protein (␤APP). Amyloid-␤ protein (A␤), the major constituent of the amyloid deposited in brain of Alzheimer's disease patients, is generated by proteolytic processing of ␤APP, which occurs in part following ␤APP internalization. Because the YENPTY motif has a role in the internalization of ␤APP, the effect of X11 binding on ␤APP processing was studied in mouse neuroblastoma N2a, human embryonic kidney 293, monkey kidney COS-1, and human glial U251 cell lines transfected with wild type or mutated ␤APP cDNAs. Secretion of soluble ␤APP via ␣-secretase activity increased significantly in cells transfected with ␤APP variants containing mutations that impair interaction with X11 when compared with cells transfected with wild type cDNA. Cotransfection of ␤APP and X11 caused retention of cellular ␤APP, decreased secretion of s␤APP␣, and decreased A␤ secretion. Thus, ␤APP interaction with the protein interaction domain of X11 stabilizes cellular ␤APP and thereby participates in the regulation of ␤APP processing pathways.Amyloid-␤ protein (A␤), 1 deposited in the brain of patients with Alzheimer's disease (AD), Down's syndrome, and sporadic and hereditary cerebral amyloid angiopathy and in the brain of elderly individuals is a proteolytic peptide of a larger ␤-amyloid precursor protein (␤APP). A␤ has been reported to have heterogeneous carboxyl termini, and A␤ 1-40 and A␤ 1-42 appear to be the major species in the parenchymal deposition. A␤ is found in normal cerebrospinal fluid and in conditioned media from various tissue culture cell lines (1-3), suggesting that it is produced and secreted constitutively. Alternative processing pathways of ␤APP have been described. Cleavage at position 597 of ␤APP 695 by a ␤-secretase results in the generation of A␤. Alternatively, processing by an ␣-secretase between positions 612 and 613 of ␤APP 695 (positions 16 and 17 of A␤) precludes the release of intact A␤ (4, 5). Both pathways result in the release of amino-terminal soluble ␤APP, s␤APP␤ and s␤APP␣, into the extracellular compartment. The carboxyl-terminal processing products may undergo an additional cleavage by a protease displaying a ␥-secretase activity leading to the formation of A␤ or P3.␣-Secretase processing of ␤APP occurs in a late compartment of the constitutive secretory pathway (6, 7), probably in a late trans-Golgi compartment (8, 9). However, ␤APP can elude the intracellular cleavage and reach the cell surface as a full-length mature product, and ␣-secretase activity may occur also at the plasma membrane in several cell systems (10, 11). Immunolabeling of cell surface ␤APP in living cells demonstrated that cell surface ␤APP is either rapidly released or internalized via clathrin-coated vesicles, such that the duration at the cell surface is very short (10,12,13). Whereas most A␤ is produced by a ␤-secretase at the cell surface (14, 15), via the endosomal/ lysosomal pathway, a sma...

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Section: Mutations That Inhibit Binding Of X11 To the Yenpty Motif Ofmentioning

confidence: 82%

X11 Interaction with β-Amyloid Precursor Protein Modulates Its Cellular Stabilization and Reduces Amyloid β-Protein Secretion

Sastre¹,

Turner²,

Levy³

1998

Journal of Biological Chemistry

131

115

View full text Add to dashboard Cite

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“…Monocytes from MS patients express higher levels of IL-1␣ and -␤ than cells from normal controls (36), and IL-1-positive glial cells are easily detected by immunohistochemistry in MS brain tissue (37). Similarly, IL-1 has been implicated in AD (38); IL-1 can induce the expression of the Alzheimer amyloid-promoting factor antichymotrypsin in astrocytes (39) and plays a role in amyloid-␤ peptide secretion (40). In these studies, microglia are considered to be the major source of CNS IL-1, but our results suggest that IL-1 can also be expressed by astrocytes through ICAM-1-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

ICAM-1-Induced Expression of Proinflammatory Cytokines in Astrocytes: Involvement of Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways

Drabik

Wagoner

et al. 2000

The Journal of Immunology

128

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ICAM-1 is a transmembrane glycoprotein of the Ig superfamily involved in cell adhesion. ICAM-1 is aberrantly expressed by astrocytes in CNS pathologies such as multiple sclerosis, experimental allergic encephalomyelitis, and Alzheimer’s disease, suggesting a possible role for ICAM-1 in these disorders. ICAM-1 has been shown to be important for leukocyte diapedesis through brain microvessels and subsequent binding to astrocytes. However, other functional roles for ICAM-1 expression on astrocytes have not been well elucidated. Therefore, we investigated the intracellular signals generated upon ICAM-1 engagement on astrocytes. ICAM-1 ligation by a mAb to rat ICAM-1 induced mRNA expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and TNF-α. Examination of cytokine protein production revealed that ICAM-1 ligation results in IL-6 secretion by astrocytes, whereas IL-1β and IL-1α protein is expressed intracellularly in astrocytes. The involvement of mitogen-activated protein kinases (MAPKs) in ICAM-1-mediated cytokine expression in astrocytes was tested, as the MAPK extracellular signal-regulated kinase (ERK) was previously shown to be activated upon ICAM-1 engagement. Our results indicate that ERK1/ERK2, as well as p38 MAPK, are activated upon ligation of ICAM-1. Studies using pharmacological inhibitors demonstrate that both p38 MAPK and ERK1/2 are involved in ICAM-1-induced IL-6 expression, whereas only ERK1/2 is important for IL-1α and IL-1β expression. Our data support the role of ICAM-1 on astrocytes as an inflammatory mediator in the CNS and also uncover a novel signal transduction pathway through p38 MAPK upon ICAM-1 ligation.

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“…Several reports describe an interaction between IL-1␤ and A␤ at the processing level; IL-1-immunoreactive microglia are prominent components of amyloid plaques in AD (4), and ␤-amyloid promotes release of IL-1␤ by the glial cells that surround senile plaques (5). In turn, IL-1␤ increases ␤APP mRNA expression (6) and promotes processing of ␤APP to liberate A␤ peptide fragments (7). Thus a chain of events involving IL-1␤ and A␤ is involved in plaque formation; however, the nature of the interaction between IL-1␤ and A␤ at a physiological level is poorly understood.…”

mentioning

confidence: 99%

Enhancement of 45Ca2+ Influx and Voltage-dependent Ca2+ Channel Activity by β-Amyloid-(1–40) in Rat Cortical Synaptosomes and Cultured Cortical Neurons

MacManus

Ramsden

Murray

et al. 2000

Journal of Biological Chemistry

126

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␤-Amyloid protein is thought to underlie the neurodegeneration associated with Alzheimer's disease by inducing Ca 2؉ -dependent apoptosis. Elevated neuronal expression of the proinflammatory cytokine interleukin-1␤ is an additional feature of neurodegeneration, and in this study we demonstrate that interleukin-1␤ modulates the effects of ␤-amyloid on Ca 2؉ homeostasis in the rat cortex. ␤-Amyloid-(1-40) (1 M) caused a significant increase in 45 Ca 2؉ influx into rat cortical synaptosomes via activation of L-and N-type voltage-dependent Ca 2؉ channels and also increased the amplitude of N-and P-type Ca 2؉ channel currents recorded from cultured cortical neurons. In contrast, interleukin-1␤ (5 ng/ml) reduced the 45 Ca 2؉ influx into cortical synaptosomes and inhibited Ca 2؉ channel activity in cultured cortical neurons. Furthermore, the stimulatory effects of ␤-amyloid protein on Ca 2؉ influx were blocked following exposure to interleukin-1␤, suggesting that interleukin-1␤ may govern neuronal responses to ␤-amyloid by regulating Ca 2؉ homeostasis.␤-Amyloid (A␤-(1-40)) 1 is a peptide fragment derived from proteolytic processing of ␤-amyloid precursor protein (␤APP) (1), which accumulates as an insoluble extracellular deposit around neurons, giving rise to the senile plaques associated with Alzheimer's disease (AD) (2). Increased neuronal expression of the proinflammatory cytokine interleukin-1␤ (IL-1␤) is an additional neuropathological hallmark of AD (3), and inflammatory mediators such as IL-1␤ have been proposed to contribute to the development of amyloid plaques (4). Several reports describe an interaction between IL-1␤ and A␤ at the processing level; IL-1-immunoreactive microglia are prominent components of amyloid plaques in AD (4), and ␤-amyloid promotes release of IL-1␤ by the glial cells that surround senile plaques (5). In turn, IL-1␤ increases ␤APP mRNA expression (6) and promotes processing of ␤APP to liberate A␤ peptide fragments (7). Thus a chain of events involving IL-1␤ and A␤ is involved in plaque formation; however, the nature of the interaction between IL-1␤ and A␤ at a physiological level is poorly understood. Neuronal apoptosis is the suspected causative factor of neurodegeneration in AD, and A␤ fragments have been shown to promote apoptosis in vitro in human-derived neurotypic cells (8) and cultured neurons (9). The mechanism underlying A␤-induced apoptosis is thought to involve disregulation of Ca 2ϩ homeostasis (10). In the C6 glial cell line, expression of the Ca 2ϩ -binding protein calbindin was found to suppress A␤-induced apoptosis (11), providing evidence for the involvement of Ca 2ϩ fluxes in A␤-induced apoptosis. In this study we report that A␤-(1-40) (i) promotes a stimulation of 45 Ca 2ϩ influx into cortical synaptosomes via activation of L-and N-type voltagedependent Ca 2ϩ channels (VDCCs) and (ii) increases the amplitude of N-and P-type VDCC current in cultured cortical neurons. Furthermore, the A␤-(1-40)-induced increase in Ca 2ϩ influx is blocked by the proinflammatory mediato...

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Interleukin‐1β dissociates β‐amyloid precursor protein and β‐amyloid peptide secretion

Cited by 33 publications

References 21 publications

X11 Interaction with β-Amyloid Precursor Protein Modulates Its Cellular Stabilization and Reduces Amyloid β-Protein Secretion

X11 Interaction with β-Amyloid Precursor Protein Modulates Its Cellular Stabilization and Reduces Amyloid β-Protein Secretion

ICAM-1-Induced Expression of Proinflammatory Cytokines in Astrocytes: Involvement of Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways

Enhancement of 45Ca2+ Influx and Voltage-dependent Ca2+ Channel Activity by β-Amyloid-(1–40) in Rat Cortical Synaptosomes and Cultured Cortical Neurons

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