Frizzled-1 receptor regulates adult hippocampal neurogenesis

Indexación: Web of Science; Scopus.Background: In the adult hippocampus new neurons are continuously generated from neural stem cells (NSCs) present at the subgranular zone of the dentate gyrus. This process is controlled by Wnt signaling, which plays a complex role in regulating multiple steps of neurogenesis including maintenance, proliferation and differentiation of progenitor cells and the development of newborn neurons. Differential effects of Wnt signaling during progression of neurogenesis could be mediated by cell-type specific expression of Wnt receptors. Here we studied the potential role of Frizzled-1 (FZD1) receptor in adult hippocampal neurogenesis. Results: In the adult dentate gyrus, we determined that FZD1 is highly expressed in NSCs, neural progenitors and immature neurons. Accordingly, FZD1 is expressed in cultured adult hippocampal progenitors isolated from mouse brain. To evaluate the role of this receptor in vivo we targeted FZD1 in newborn cells using retroviral-mediated RNA interference. FZD1 knockdown resulted in a marked decrease in the differentiation of newborn cells into neurons and increased the generation of astrocytes, suggesting a regulatory role for the receptor in cell fate commitment. In addition, FZD1 knockdown induced an extended migration of adult-born neurons within the granule cell layer. However, no differences were observed in total dendritic length and dendritic arbor complexity between control and FZD1-deficient newborn neurons. Conclusions: Our results show that FZD1 regulates specific stages of adult hippocampal neurogenesis, being required for neuronal differentiation and positioning of newborn neurons into the granule cell layer, but not for morphological development of adult-born granule neurons.https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-016-0209-

Age-dependent increases in apoptosis/necrosis ratios in human lymphocytes exposed to oxidative stress

Unlike apoptosis, mechanisms leading to necrosis are less well understood. Moreover, changes in necrosis as a function of age have not been studied in human lymphocytes. H 2O 2-induced death of peripheral lymphocytes (56 healthy donors, 24-95 years) was evaluated by flow cytometry and propidium iodide staining, caspase activation, DNA laddering, and electron microscopy. H 2O 2-induced stress was associated with high levels of necrosis in young individuals (≤30 years), whereas progressively enhanced apoptotic death was observed in older donors, without changes in overall lymphocyte survival. Thus, apoptosis/necrosis ratios were inverted in young versus elderly (≥65 years) donors. Death was not accompanied by increased caspase activity and, accordingly, unaffected by caspase inhibition; however, it was almost completely prevented by poly ADP ribose polymerase inhibition. In summary, aging was associated with changes in the apoptosis/necrosis ratios, rather than susceptibility per se to

Tumor-induced osteomalacia: experience from a South American academic center

The majority of tumor-induced osteomalacia cases have been reported in the Northern Hemisphere and Asia. In this first series of South American patients, we show that the clinical presentation and sensitivity of plasmatic fibroblast growth factor 23 and somatostatin analog-based imaging are similar to those described in other populations. Describe the experience of clinical presentation, diagnostic study, and treatment of patients with tumor-induced osteomalacia (TIO) in a South American academic center in comparison to literature. Analysis of the records of patients diagnosed with TIO. The clinical presentation, diagnostic studies, and treatment were analyzed. Fibroblast growth factor 23 (FGF23) was measured by ELISA. Six patients were diagnosed with TIO during the studied period. The patients' median age was 53 years (range 22-64). All patients presented with weakness and pain in the extremities. Four experienced fractures during their evolution. The median time to diagnosis was 4.5 years (1-20). Biochemical studies showed hypophosphatemia, median of 1.4 mg/dL (1.2-1.6), with low maximum rates of tubular reabsorption of phosphate adjusted for glomerular filtration rate. FGF23 was elevated in 4/6 patients and inappropriately normal in the other two. In three patients, the location of the tumor was clinically evident and confirmed with anatomical imaging. In the remaining patients, two tumors were located with Ga-68 DOTATATE-PET/CT and one with OctreoScan. The causal tumors were located in the lower extremities in five patients and invading the frontal sinus in one patient. In all patients, tumors were successfully removed. Within 14 days, there was normalization of phosphate and FGF23 levels and resolution of clinical symptoms in all patients. In all cases, the histopathology was compatible with a phosphaturic mesenchymal tumor. The clinical presentation, delay time to diagnosis, FGF23 diagnostic sensitivity and histopathology in this first series of South American patients is similar to those described in other populations. The success of localization by somatostatin analog-based imaging, suggests this may the optimal imaging modality.Research Direction of the Faculty of Medicine, Pontificia Universidad Catolica de Chil

Increased susceptibility to oxidative death of lymphocytes from Alzheimer patients correlates with dementia severity

© 2014 Bentham Science Publishers.We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer’s disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer’s disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1- 2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining

Inverse susceptibility to oxidative death of lymphocytes obtained from Alzheimer's patients and skin cancer survivors: Increased apoptosis in Alzheimer's and reduced necrosis in cancer

A paucity of cancer in individuals with Alzheimer's disease (AD) and low rates of AD in cancer survivors has been reported in epidemiological studies. Deregulation in opposite directions of biological mechanisms, such as susceptibility to cell death, might be shared in the two disorders. We analyzed lymphocytes from AD and skin cancer patients as well as healthy controls and found significantly increased vulnerability of AD lymphocytes to H2O2-induced apoptotic death and higher resistance to death of skin cancer lymphocytes, due to reduced necrosis, as compared with healthy controls by pairwise comparisons adjusted for age and sex. H2O2-induced death in lymphocytes was caspase independent and significantly reduced by PARP-1 inhibition in all three groups. These differences in the susceptibility to cell death observed for lymphocytes from AD and skin cancer patients may be one of the mechanisms that help explain the inverse correlation detected between these diseases in epidemiologica