scholarly journals Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils

2007 ◽  
Vol 18 (4) ◽  
pp. 1490-1496 ◽  
Author(s):  
Amitabha Majumdar ◽  
Dana Cruz ◽  
Nikiya Asamoah ◽  
Adina Buxbaum ◽  
Istvan Sohar ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Primary Mouse ◽  
Macrophage Colony Stimulating Factor ◽  
Lysosomal Proteases ◽  
Macrophage Colony ◽  
Kinase A

Microglia are the main immune cells of the brain, and under some circumstances they can play an important role in removal of fibrillar Alzheimer amyloid β peptide (fAβ). Primary mouse microglia can internalize fAβ, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fAβ efficiently, and we found that microglia actually contain higher levels of many lysosomal proteases than macrophages. However, the microglial lysosomes are less acidic (average pH of ∼6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with macrophage colony-stimulating factor (MCSF) or interleukin-6 acidify the lysosomes of microglia and enable them to degrade fAβ. After treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH of ∼5), and the MCSF-induced acidification can be partially reversed upon treatment with an inhibitor of protein kinase A or with an anion transport inhibitor. Microglia also degrade fAβ if lysosomes are acidified by an ammonia pulse-wash or by treatment with forskolin, which activates protein kinase A. Our results indicate that regulated lysosomal acidification can potentiate fAβ degradation by microglia.

scholarly journals GnRH Pulse Frequency Control of Fshb Gene Expression Is Mediated via ERK1/2 Regulation of ICER

2016 ◽  
Vol 30 (3) ◽  
pp. 348-360 ◽  
Author(s):  
Iain R. Thompson ◽  
Nick A. Ciccone ◽  
Qiongjie Zhou ◽  
Shuyun Xu ◽  
Ahmad Khogeer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathways ◽  
Frequency Control ◽  
Mitogen Activated Protein Kinase ◽  
Low Frequencies ◽  
Pulsatile Gnrh ◽  
Primary Mouse ◽  
Kinase A

Abstract The pulsatile release of GnRH regulates the synthesis and secretion of pituitary FSH and LH. Two transcription factors, cAMP-response element-binding protein (CREB) and inducible cAMP early repressor (ICER), have been implicated in the regulation of rat Fshb gene expression. We previously showed that the protein kinase A pathway mediates GnRH-stimulated CREB activation. We hypothesized that CREB and ICER are activated by distinct signaling pathways in response to pulsatile GnRH to modulate Fshb gene expression, which is preferentially stimulated at low vs high pulse frequencies. In the LβT2 gonadotrope-derived cell line, GnRH stimulation increased ICER mRNA and protein. Blockade of ERK activation with mitogen-activated protein kinase kinase I/II (MEKI/II) inhibitors significantly attenuated GnRH induction of ICER mRNA and protein, whereas protein kinase C, calcium/calmodulin-dependent protein kinase II, and protein kinase A inhibitors had minimal effects. GnRH also stimulated ICER in primary mouse pituitary cultures, attenuated similarly by a MEKI/II inhibitor. In a perifusion paradigm, MEKI/II inhibition in LβT2 cells stimulated with pulsatile GnRH abrogated ICER induction at high GnRH pulse frequencies, with minimal effect at low frequencies. MEKI/II inhibition reduced GnRH stimulation of Fshb at high and low pulse frequencies, suggesting that the ERK pathway has additional effects on GnRH regulation of Fshb, beyond those mediated by ICER. Indeed, induction of the activating protein 1 proteins, cFos and cJun, positive modulators of Fshb transcription, by pulsatile GnRH was also abrogated by inhibition of the MEK/ERK signaling pathway. Collectively, these studies indicate that the signaling pathways mediating GnRH activation of CREB and ICER are distinct, contributing to the decoding of the pulsatile GnRH to regulate FSHβ expression.

AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure

2011 ◽  
Vol 434 (3) ◽  
pp. 503-512 ◽  
Author(s):  
Claire Thornton ◽  
Nicola J. Bright ◽  
Magdalena Sastre ◽  
Phillip J. Muckett ◽  
David Carling
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Primary Mouse ◽  
Cellular Stresses ◽  
Amp Activated Protein Kinase

Hyperphosphorylation of tau is a hallmark of Alzheimer's disease and other tauopathies. Although the mechanisms underlying hyperphosphorylation are not fully understood, cellular stresses such as impaired energy metabolism are thought to influence the signalling cascade. The AMPK (AMP-activated protein kinase)-related kinases MARK (microtubule-associated protein-regulating kinase/microtubule affinity-regulating kinase) and BRSK (brain-specific kinase) have been implicated in tau phosphorylation, but are insensitive to activation by cellular stress. In the present study, we show that AMPK itself phosphorylates tau on a number of sites, including Ser262 and Ser396, altering microtubule binding of tau. In primary mouse cortical neurons, CaMKKβ (Ca2+/calmodulin-dependent protein kinase kinase β) activation of AMPK in response to Aβ (amyloid-β peptide)-(1–42) leads to increased phosphorylation of tau at Ser262/Ser356 and Ser396. Activation of AMPK by Aβ-(1–42) is inhibited by memantine, a partial antagonist of the NMDA (N-methyl-D-aspartate) receptor and currently licensed for the treatment of Alzheimer's disease. These findings identify a pathway in which Aβ-(1–42) activates CaMKKβ and AMPK via the NMDA receptor, suggesting the possibility that AMPK plays a role in the pathophysiological phosphorylation of tau.

scholarly journals Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes

2011 ◽  
Vol 22 (10) ◽  
pp. 1664-1676 ◽  
Author(s):  
Amitabha Majumdar ◽  
Estibaliz Capetillo-Zarate ◽  
Dana Cruz ◽  
Gunnar K. Gouras ◽  
Frederick R. Maxfield
Keyword(s):  
Amyloid Fibrils ◽  
Ph Regulation ◽  
Amyloid Β ◽  
Degradation Pathway ◽  
Amyloid Β Peptide ◽  
Lysosomal Ph ◽  
Activated Microglia ◽  
Pathway Activation ◽  
Macrophage Colony ◽  
Lysosomal Acidification

Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid β peptide (fAβ). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum–associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAβ degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAβ degradation.

Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽  
2000 ◽  
pp. 377-383 ◽  
Author(s):  
L Leonardsen ◽  
A Wiersma ◽  
M Baltsen ◽  
AG Byskov ◽  
CY Andersen
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Mouse Oocytes ◽  
Mitogen Activated Protein ◽  
Dependent Signal ◽  
Kinase Pathway ◽  
Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

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