Numb chin syndrome: What all oral health care professionals should know.

BACKGROUND: Numb chin syndrome (NCS) is a rare sensory neuropathy involving the mental nerve. Symptoms of NCS are often overlooked because of their apparent innocent nature; however, owing to the frequent association of NCS with malignancies, the opposite should be the rule. Oral health care professionals may be the first to encounter patients with NCS and should be aware of its clinical characteristics in an effort to decrease patient morbidity and mortality. TYPES OF STUDIES REVIEWED: A search in PubMed (MEDLINE) and the Cochrane Library was performed using the terms numb chin syndrome, numb chin, mental neuropathy, mental nerve neuropathy, and malignant mental nerve neuropathy, yielding 2,374 studies. After inclusion and exclusion criteria were applied, 102 studies remained. Descriptive statistics were performed, analyzing the etiology responsible for NCS, characteristics of NCS including associated symptoms, unilateral or bilateral nature, and information on professionals visited and examinations requested to make a diagnosis. RESULTS: NCS was associated with malignancy in 29% through 53% of the published cases. Twenty-eight percent of patients initially consulted an oral health care professional with the symptom of a numb chin. Patients more likely to have NCS were those from the ages of 61 through 70 years; 74% were unilateral; and the most common symptoms reported were numbness (100%), paresthesia (18%), and pain (17%). Forty-seven percent of the NCS cases were associated with a recurrent malignancy, and the most prevalent associated diagnoses were breast cancer (32%) and lymphoma and leukemia (24%). CONCLUSIONS: Oral health care professionals should be aware of the characteristics of NCS as they may be the first health care providers consulted for these symptoms. PRACTICAL IMPLICATIONS: A thorough medical and dental history as well as a complete cranial nerve screening should be performed on all patients, especially those with numbness, as this may prevent misdiagnosis and allow a timely referral and a substantial improvement of treatment course and prognosis.

24 hour polymerization shrinkage of resin composite core materials.

PURPOSE: The study's purpose was to evaluate the 24-hour polymerization shrinkage of resin composite core materials. MATERIAL AND METHODS: Eleven resin composite core material samples (n = 12) were evaluated using a non-contact imaging device with measurements obtained over 24 h. Shrinkage values were determined corresponding to proposed times involved with CAD/CAM same-day treatment and at 24 h. Shrinkage data was statistically compared using Friedman/Dunn's test for intragroup analysis and Kruskal Wallis/Dunn's test for intergroup analysis, all at a 95% level of confidence (α = 0.05). RESULTS: Mean results identified a wide volumetric shrinkage range with considerable similarity overlap. Inconsistent shrinkage behavior was evident and all materials reached maximum values before 24 h. No significant difference was observed during proposed digital same day all ceramic crown procedures, but some differences were noted at 24 h. CONCLUSIONS: Under this study's conditions results were material specific, at times inconsistent, with wide variation. Shrinkage consistently increased for all products and it is not known if the continued shrinkage magnitude may compromise the stability and fit of all-ceramic crowns at 24 h.

Microtomographic Analysis of Resin Composite Core Material Porosity.

PURPOSE: To nondestructively evaluate the porosity of ten contemporary resin composite core materials using microtomographic (microCT) analysis. MATERIAL AND METHODS: Resin composite core material samples (n = 12) including dual-cure, visible light cure only, and a self-cure material were fabricated using a standardized mold following manufacturer's recommendations. After storage in phosphate buffered saline for one week, specimens were analyzed using a microCT unit at 5.3-µm resolution over a rotational range of 360°. Image 3D recombination and analysis was accomplished using microCT software. Evaluated parameters included material volume investigated, closed pore number and volume, as well as closed pore percentage. Parameter mean values were evaluated with Kruskal-Wallis/Dunn at a 95% confidence level (α = 0.05). RESULTS: Mean percent total porosity with standard deviation identified significant differences in decreasing order as Ti-Core: 2.2 (0.4) > Ti-Core Auto E: 1.3 (0.3) = Ti-Core Flow Plus: 1.1 (0.02) > Clearfil Photo Core: 0.94 (0.5) = Clearfil DC Core Plus: 0.6 (0.18) = MultiCore Flow: 0.58 (0.1) > Fluorocore 2+: 0.14 (0.2) = Build-It FR: 0.068 (0.02) = Gradia Core: 0.03 (0.02) = Rebilda DC: 0.02 (0.01). A pilot microCT evaluation evaluating a mixing tip revealed incomplete mixture between the two resins with porosity introduced from turbulence as the materials are forced through the tip during preparation. CONCLUSIONS: A wide range of porosity was identified between the ten materials evaluated. These preliminary results warrant more investigation evaluating additional resin composite core materials, the preparation capabilities of automix tips, and porosity presence in the unmixed materials.

Emerging new role of NFAT5 in inducible nitric oxide synthase in response to hypoxia in mouse embryonic fibroblast cells.

We previously described the protective role of the nuclear factor of activated T cells 5 (NFAT5) during hypoxia. Alternatively, inducible nitric oxide synthase (iNOS) is also induced by hypoxia. Some evidence indicates that NFAT5 is essential for the expression of iNOS in Toll-like receptor-stimulated macrophages and that iNOS inhibition increases NFAT5 expression in renal ischemia-reperfusion. Here we studied potential NFAT5 target genes stimulated by hypoxia in mouse embryonic fibroblast (MEF) cells. We used three types of MEF cells associated with NFAT5 gene: NFAT5 wild type (MEF-NFAT5+/+), NFAT5 knockout (MEF-NFAT5-/-), and NFAT5 dominant-negative (MEF-NFAT5Δ/Δ) cells. MEF cells were exposed to 21% or 1% O2 in a time course curve of 48 h. We found that, in MEF-NFAT5+/+ cells exposed to 1% O2, NFAT5 was upregulated and translocated into the nuclei, and its transactivation domain activity was induced, concomitant with iNOS, aquaporin 1 (AQP-1), and urea transporter 1 (UTA-1) upregulation. Interestingly, in MEF-NFAT5-/- or MEF-NFAT5Δ/Δ cells, the basal levels of iNOS and AQP-1 expression were strongly downregulated, but not for UTA-1. The upregulation of AQP-1, UTA-1, and iNOS by hypoxia was blocked in both NFAT5-mutated cells. The iNOS induction by hypoxia was recovered in MEF-NFAT5-/- MEF cells, when recombinant NFAT5 protein expression was reconstituted, but not in MEF-NFAT5Δ/Δ cells, confirming the dominant-negative effect of MEF-NFAT5Δ/Δ cells. We did not see the rescue effect on AQP-1 expression. This work provides novel and relevant information about the signaling pathway of NFAT5 during responses to oxygen depletion in mammalian cells and suggests that the expression of iNOS induced by hypoxia is dependent on NFAT5.

Influencia de la etnia mapuche sobre la indicación de terapia hormonal de la menopausia según aplicación escala de calidad de vida (mrs), en población rural de la araucanía / Influence of the Mapuche ethnic group on the indication of hormonal therapy for menopause according to the application of the quality of life scale (mrs), in a rural population of Araucanía

RESUMEN Objetivo: Relacionar la pertenencia a la etnia Mapuche y los síntomas climatéricos de indicación de Terapia Hormonal de la Menopausia (THM), en una población del sector rural de Boyeco, región de La Araucanía. Materiales y métodos: Estudio observacional realizado en mujeres rurales en control de salud en CESFAM Boyeco entre octubre de 2016 y enero de 2017. Ninguna de las participantes evaluadas recibía THM. Para el estudio, se consideró el número de apellidos mapuches. Se utilizó el instrumento validado para población chilena, "Escala MRS" (Menopause Rating Scale), el cual permite discriminar los diferentes dominios sintomáticos del climaterio. Resultados: El grupo en estudio lo componen 36 mujeres de 41 a 78 años de edad, promedio (DE) 52,8(8,6) años, un 52,8% tiene dos apellidos mapuches y 25% uno. Un 92,8% de las mujeres mapuche tiene indicación de terapia, versus todas las no mapuche. En las menores de 50 años, todas tiene indicación de terapia, frente a un 71,4% en las mayores de 50 años. Conclusiones: Las pacientes mapuches tienen mayor sintomatología en los dominios somáticos y psicológicos, especialmente aquellas bajo 50 años. Todas las mujeres estudiadas bajo 50 años requieren terapia, sin variación estadísticamente significativa x etnicidad.

SUMMARY Objective: To stablish the relationship between belonging to Mapuche ethnic group on the climacteric symptoms for indication of menopause hormone therapy (HTM), in the rural population of Boyeco, inside of Araucania's region, Chile. Materials and methods: An observational and descriptive study, in a sample in time of 36 women belonging to the sector who attended CESFAM Boyeco, between October 2016 and January 2017. None of the evaluated participants received THM. As exposure variable, it was considered the number the mapuche surnames. We used the Menopause Rating Scale (MRS), an international instrument validated for Chilean population, to discriminate the different symptomatic domains of the climacteric period. Results: 94.7% of mapuche women and all non-mapuche population had prescribed hormonal therapy. Independent of ethnicity, those under 50 years of age, 100% have an indication for therapy compared to 71.4% in those over 50 years of age. Conclusions: Mapuche patients have greater symptomatology in the somatic-psychological domains, especially in those under 50 years of age. The totality of women under 50 requires therapy, however, variation according to ethnicity.

Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?

Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies.

Overexpression of Glutamate Decarboxylase in Mesenchymal Stem Cells Enhances Their Immunosuppressive Properties and Increases GABA and Nitric Oxide Levels.

The neurotransmitter GABA has been recently identified as a potent immunosuppressive agent that targets both innate and adaptive immune systems and prevents disease progression of several autoimmunity models. Mesenchymal stem cells (MSCs) are self-renewing progenitor cells that differentiate into various cell types under specific conditions, including neurons. In addition, MSC possess strong immunosuppressive capabilities. Upon cytokine priming, undifferentiated MSC suppress T-cell proliferation via cell-to-cell contact mechanisms and the secretion of soluble factors like nitric oxide, prostaglandin E2 and IDO. Although MSC and MSC-derived neuron-like cells express some GABAergic markers in vitro, the role for GABAergic signaling in MSC-mediated immunosuppression remains completely unexplored. Here, we demonstrate that pro-inflammatory cytokines selectively regulate GAD-67 expression in murine bone marrow-MSC. However, expression of GAD-65 is required for maximal GABA release by MSC. Gain of function experiments using GAD-67 and GAD-65 co-expression demonstrates that GAD increases immunosuppressive function in the absence of pro-inflammatory licensing. Moreover, GAD expression in MSC evokes an increase in both GABA and NO levels in the supernatants of co-cultured MSC with activated splenocytes. Notably, the increase in NO levels by GAD expression was not observed in cultures of isolated MSC expressing GAD, suggesting crosstalk between these two pathways in the setting of immunosuppression. These results indicate that GAD expression increases MSC-mediated immunosuppression via secretion of immunosuppressive agents. Our findings may help reconsider GABAergic activation in MSC for immunological disorders.

Intravenous administration of bone marrow-derived mesenchymal stem cells induces a switch from classical to atypical symptoms in experimental autoimmune encephalomyelitis.

Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis.

Esthetic failure in implant dentistry.

The definition of failure for dental implants has evolved from lack of osseointegration to increased concern for other aspects, such as esthetics. However, esthetic failure in implant dentistry has not been well defined. Although multiple esthetic indices have been validated for objectively evaluating clinical outcomes, including failure of an implant-supported crown, only one author has determined a failure threshold. On the basis of objective indices, esthetic failures in implant dentistry can be categorized as pink-tissue failures and white-tissue failures. This article discusses esthetic failures, the factors involved in these failures, and their prevention and treatment.

An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors.

Intracellular protein aggregation is a common pathologic feature in neurodegenerative diseases such as Huntington' disease, amyotrophic lateral sclerosis and Parkinson' disease. Although progress towards understanding protein aggregation in vitro has been made, little of this knowledge has translated to patient therapy. Moreover, mechanisms controlling aggregate formation and catabolism in cellulo remain poorly understood. One limitation is the lack of tools to quantitatively monitor protein aggregation and disaggregation. Here, we developed a protein-aggregation reporter that uses huntingtin exon 1 containing 72 glutamines fused to the N-terminal end of firefly luciferase (httQ72-Luc). httQ72-Luc fails to aggregate unless seeded by a non-luciferase-containing polyglutamine (polyQ) protein such as Q80-cfp. Upon co-aggregation, httQ72-luc becomes insoluble and loses its enzymatic activity. Using httQ72-Luc with Q80(CFP/YFP) as seeds, we screened the Johns Hopkins Clinical Compound Library and identified leflunomide, a dihydroorotate dehydrogenase inhibitor with immunosuppressive and anti-psoriatic activities, as a novel drug that prevents polyQ aggregation. Leflunomide and its active metabolite teriflunomide inhibited protein aggregation independently of their known role in pyrimidine biosynthesis, since neither uridine treatment nor other pyrimidine biosynthesis inhibitors affected polyQ aggregation. Inducible cell line and cycloheximide-chase experiments indicate that these drugs prevent incorporation of expanded polyQ into an aggregate. This study demonstrates the usefulness of luciferase-based protein aggregate reporters for high-throughput screening applications. As current trials are under-way for teriflunomide in the treatment of multiple sclerosis, we propose that this drug be considered a possible therapeutic agent for polyQ diseases.

Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking.

BACKGROUND: Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-beta 42 (Abeta42) that precede extracellular amyloid deposition in vulnerable brain regions. It has been hypothesized that endosomal/lysosomal dysfunction might be associated with the pathological accumulation of intracellular Abeta42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal Abeta42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of Abeta42 through LRP1 is lacking. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that LRP1 endocytic function is required for neuronal Abeta42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases Abeta42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal Abeta42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of Abeta42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of Abeta42 is associated with increased cellular toxicity. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that LRP1 endocytic function plays an important role in the uptake and accumulation of Abeta42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal Abeta metabolism.

Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43.

The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.

Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase-inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway.

The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-beta peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-beta-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.

Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons.

Wnt signaling is essential for neuronal development and the maintenance of the developing nervous system. Recent studies indicated that Wnt signaling modulates long term potentiation in adult hippocampal slices. We report here that different Wnt ligands are present in hippocampal neurons of rat embryo and adult rat, including Wnt-4, -5a, -7a, and -11. Wnt-7a acts as a canonical Wnt ligand in rat hippocampal neurons, stimulates clustering of presynaptic proteins, and induces recycling and exocytosis of synaptic vesicles as studied by FM dyes. Wnt-3a has a moderate effect on recycling of synaptic vesicles, and no effect of Wnt-1 and Wnt-5a was detected. Electrophysiological analysis on adult rat hippocampal slices indicates that Wnt-7a, but not Wnt-5a, increases neurotransmitter release in CA3-CA1 synapses by decreasing paired pulse facilitation and increasing the miniature excitatory post-synaptic currents frequency. These results indicate that the presynaptic function of rat hippocampal neurons is modulated by the canonical Wnt signaling.

Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been proposed as a therapeutic target for neurodegenerative diseases because of its anti-inflammatory action in glial cells. However, PPARgamma agonists preventbeta-amyloid (Abeta)-induced neurodegeneration in hippocampal neurons, and PPARgamma is activated by the nerve growth factor (NGF) survival pathway, suggesting a neuroprotective anti-inflammatory independent action. Here we show that the PPARgamma agonist rosiglitazone (RGZ) protects hippocampal and dorsal root ganglion neurons against Abeta-induced mitochondrial damage and NGF deprivation-induced apoptosis, respectively, and promotes PC12 cell survival. In neurons and in PC12 cells RGZ protective effects are associated with increased expression of the Bcl-2 anti-apoptotic protein. NGF-differentiated PC12 neuronal cells constitutively overexpressing PPARgamma are resistant to Abeta-induced apoptosis and morphological changes and show functionally intact mitochondria and no increase in reactive oxygen species when challenged with up to 50 microM H2O2. Conversely, cells expressing a dominant negative mutant of PPARgamma show increased Abeta-induced apoptosis and disruption of neuronal-like morphology and are highly sensitive to oxidative stress-induced impairment of mitochondrial function. Cells overexpressing PPARgamma present a 4- to 5-fold increase in Bcl-2 protein content, whereas in dominant negative PPARgamma-expressing cells, Bcl-2 is barely detected. Bcl-2 knockdown by small interfering RNA in cells overexpressing PPARgamma results in increased sensitivity to Abeta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPARgamma protective effects. PPARgamma prosurvival action is independent of the signal-regulated MAPK or the Akt prosurvival pathways. Altogether, these data suggest that PPARgamma supports survival in neurons in part through a mechanism involving increased expression of Bcl-2.

ApoER2 expression increases Abeta production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of gamma-secretase activity.

BACKGROUND: The generation of the amyloid-beta peptide (Abeta) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing. RESULTS: Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Unexpectedly, ApoER2 expression correlated with a significant increase in Abeta production and reduced levels of APP-CTFs. The increased Abeta production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. We also found that expression of ApoER2 increased APP association with lipid rafts and increased gamma-secretase activity, both of which might contribute to increased Abeta production. CONCLUSION: These findings show that ApoER2 negatively affects APP internalization. However, ApoER2 expression stimulates Abeta production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting beta-secretase and gamma-secretase mediated amyloidogenic processing and also by incrementing the activity of gamma-secretase.

Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive dementia accompanied by two main structural changes in the brain: intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular amyloid protein deposits surrounded by dystrophic neurites that constitutes the senile plaques. Currently, it is widely accepted that amyloid beta-peptide (A beta) metabolism disbalance is crucial for AD progression. A beta deposition may be enhanced by molecular chaperones, including metals like copper and proteins like acetylcholinesterase (AChE). At the neuronal level, several AD-related proteins interact with transducers of the Wnt/beta-catenin signaling pathway, including beta-catenin and glycogen synthase kinase 3 beta (GSK-3 beta) and both in vitro and in vivo studies suggest that Wnt/beta-catenin signaling is a target for A beta toxicity. Accordingly, activation of this signaling by lithium or Wnt ligands in AD-experimental animal models or in primary hippocampal neurons attenuate A beta neurotoxicity by recovering beta-catenin levels and Wnt-target gene expression of survival genes such as bcl-2. On the other hand, peroxisomal proliferator-activated receptor gamma (PPAR gamma) and muscarinic acetylcholine receptor (mAChR) agonists also activate Wnt/beta-catenin signaling and they have neuroprotective effects on hippocampal neurons. Our studies are consistent with the idea that a sustained loss of function of Wnt signaling components would trigger a series of events, determining the onset and development of AD and that modulation of this pathway through the activation of cross-talking signaling cascades should be considered as a possible therapeutic strategy for AD treatment.