Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease

Rutas de señalización intracelular que regulan la apoptosis inducida por lovastatina en neuroblastos fetales de rata

The aim of this Thesis has been to study the intracellular signals and molecular mechanisms that control neuronal apoptosis. We have mainly focused our attention to the survival pathways Duch as RAS/RAF/MAP-kinases, PI3-K/PKB, as well as death pathways, stress-activated MAP-kinases (JUN-kinases and p38).El objeto de esta Tesis ha sido estudiar las señales intracelulares y los mecanismos moleculares que controlan el proceso de apoptosis en las células neuronales. En concreto se ha estudiado el efecto de la lovastatina en las rutas de transducción de señales, principalmente en las rutas reguladoras de la supervivencia celular como las de RAS/RAF/MAP-quinasas y PI3-K/PKB, así como en las rutas mediadoras de muerte celular, MAP-quinasas activadas por estrés (JUN-quinasas y p38)

MAPK12 (mitogen-activated protein kinase 12)

Review on MAPK12 (mitogen-activated protein kinase 12), with data on DNA, on the protein encoded, and where the gene is implicated

MAPK13 (mitogen-activated protein kinase 13)

Review on MAPK13 (mitogen-activated protein kinase 13), with data on DNA, on the protein encoded, and where the gene is implicated

p38 MAPK down-regulates fibulin 3 expression through methylation of gene regulatory sequences: role in migration and invasion

p38 MAPKs regulate migration and invasion. However, the mechanisms involved are only partially known. We had previously identified fibulin 3, which plays a role in migration, invasion, and tumorigenesis, as a gene regulated by p38α. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38α, p38γ, and p38δ down-regulate fibulin 3 expression. p38αhas a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by theDNAmethylase, DNMT3A, which is down-regulated in cells lacking p38α, but once re-introduced represses Fibulin 3 expression. p38α through HuR stabilizes dnmt3a mRNA leading to an increase in DNMT3A protein levels. Moreover, by knocking-down fibulin 3, we have found that Fibulin 3 inhibits migration and invasion in MEFs by mechanisms involving p38α/β inhibition. Hence, p38α pro-migratory/invasive effect might be, at least in part, mediated by fibulin 3 down-regulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38α and/or p38β activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38α, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38α limits fibulin 3 expression, which might represent a negative feed-back loop.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2010-20918-C02-01 and SAF2103-48210-C2-02 (to A. P.), SAF2010-20918-C02-02, SAF2103-48210-C2-01 (to C. G.)) and from the Council of Health and Social Welfare and the Council of Education from Junta de Castilla y León (SA157A12-1, to C. G.), Spain. All funding was cosponsored by the European FEDER Program. This work was also supported by the Spanish Ministry of Education (FPU fellowship) (to M. A. and N. P.) and the Spanish Ministry of Economy and Competitiveness (to A. V.).Peer Reviewe

Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts

We have shown previously that lovastatin, a 3-hydroxy-3-methyl- glutaryl coenzyme A reductase inhibitor, induces apoptosis in spontaneously immortalized rat brain neuroblasts. In the present study, we analysed the intracellular signal transduction pathways by which lovastatin induces neuroblast apoptosis. We showed that lovastatin efficiently inhibited Ras activation, which was associ-ated with a significant decrease in ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Lovastatin also decreased CREB phosphorylation and CREB-mediated gene expression. The effects of lovastatin on the Ras/ERK1/2/CREB pathway were time- and concentration-dependent and fully prevented by meva-lonate. In addition, we showed that two MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] inhibitors, PD98059 and PD184352, were poor inducers of apoptosis in serum-treated neuroblasts. However, these inhibitors significantly increased apop-tosis induced by lovastatin treatment. Furthermore, we showed that pharmacological inhibition of both MEK and phosphoinos-itide 3-kinase activities was able to induce neuroblast apoptosis with similar efficacy as lovastatin. Our results suggest that lovast-atin triggers neuroblast apoptosis by regulating several signalling pathways, including the Ras/ERK1/2 pathway. These findings might also contribute to elucidate the intracellular mechanisms involved in the central nervous system side effects associated with statin therapy