Neuronal deficiency of p38α-MAPK ameliorates symptoms and pathology of APP or Tau-transgenic Alzheimer's mouse models.

Alzheimer's disease (AD) is the leading cause of dementia with very limited therapeutic options. Amyloid ß (Aß) and phosphorylated Tau (p-Tau) are key pathogenic molecules in AD. P38α-MAPK is specifically activated in AD lesion sites. However, its effects on AD pathogenesis, especially on p-Tau-associated brain pathology, and the underlying molecular mechanisms remain unclear. We mated human APP-transgenic mice and human P301S Tau-transgenic mice with mapk14-floxed and neuron-specific Cre-knock-in mice. We observed that deletion of p38α-MAPK specifically in neurons improves the cognitive function of both 9-month-old APP and Tau-transgenic AD mice, which is associated with decreased Aß and p-Tau load in the brain. We further used next-generation sequencing to analyze the gene transcription in brains of p38α-MAPK deficient and wild-type APP-transgenic mice, which indicated that deletion of p38α-MAPK regulates the transcription of calcium homeostasis-related genes, especially downregulates the expression of grin2a, a gene encoding NMDAR subunit NR2A. Cell culture experiments further verified that deletion of p38α-MAPK inhibits NMDA-triggered calcium influx and neuronal apoptosis. Our systemic studies of AD pathogenic mechanisms using both APP- and Tau-transgenic mice suggested that deletion of neuronal p38α-MAPK attenuates AD-associated brain pathology and protects neurons in AD pathogenesis. This study supports p38α-MAPK as a novel target for AD therapy.

Poly(4-vinylaniline)/Polyaniline Bilayer-Functionalized Bacterial Cellulose for Flexible Electrochemical Biosensors.

A bacterial cellulose (BC) nanofibril network is modified with an electrically conductive polyvinylaniline/polyaniline (PVAN/PANI) bilayer for construction of potential electrochemical biosensors. This is accomplished through surface-initiated atom transfer radical polymerization of 4-vinylaniline, followed by in situ chemical oxidative polymerization of aniline. A uniform coverage of the BC nanofiber with 1D supramolecular PANI nanostructures is confirmed by Fourier transform infrared, X-ray diffractogram, and CHN elemental analysis. Cyclic voltammograms evince the switching in the electrochemical behavior of BC/PVAN/PANI nanocomposites from the redox peaks at 0.74 V, in the positive scan and at -0.70 V, in the reverse scan, (at 100 mV·s-1 scan rate). From these redox peaks, PANI is the emeraldine form with the maximal electrical performance recorded, showing charge-transfer resistance as low as 21 Ω and capacitance as high as 39 µF. The voltage-sensible nanocomposites can interact with neural stem cells isolated from the subventricular zone (SVZ) of the brain, through stimulation and characterization of differentiated SVZ cells into specialized and mature neurons with long neurites measuring up to 115 ± 24 µm length after 7 days of culture without visible signs of cytotoxic effects. The findings pave the path to the new effective nanobiosensor technologies for nerve regenerative medicine, which demands both electroactivity and biocompatibility.

Proinflammatory cytokines induce neurotrophic factor expression in enteric glia: a key to the regulation of epithelial apoptosis in Crohn's disease.

OBJECTIVES: Imbalanced apoptosis of enterocytes is likely to be 1 of the mechanisms underlying Crohn's disease (CD). Apoptosis of enterocytes is regulated by glial-derived neurotrophic factor (GDNF), which is increased in CD. The cellular source of GDNF during gut inflammation is unclear. The aim of the study was to identify the source of GDNF in CD during gut inflammation. MATERIALS AND METHODS: Glial fibrillary acidic protein (GFAP), GDNF, and smooth muscle actin (SMA) was detected in the gut from patients with CD by immunohistochemistry. Cultured enteric glia cells (EGC) were labeled with anti-GFAP, anti-GDNF, and antibodies and a Golgi marker (anti-58K antibodies) after blocking Golgi export with monensin. Cultured EGCs were treated with interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and lipopolysaccharides. Secretion of neurotrophic factors was detected by enzyme-linked immunosorbent assay. RESULTS: Mucosal GFAP-positive EGCs are increased in the colon of patients with CD. This type of glia but not subepithelial myofibroblasts expresses significant amounts of GDNF. In vitro GDNF is continuously secreted from cultured EGCs. The neurotrophic factor secretion could be stimulated by IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharides in a time- and dose-dependent manner. The increased GDNF secretion by EGCs sustained for>12 hours after withdrawal of the proinflammatory cytokines. CONCLUSIONS: A mucosal GFAP expressing EGC population is dramatically increased in CD. This population is a major cellular source of the upregulated GDNF in the inflamed gut. Therefore, mucosal EGC may play a key role in protecting the gut epithelium and may contribute to reestablish the integrity of the injured epithelium.

Development of multi scale structured Al/AI2O3 nanowires for controlled cell guidance.

Cell responses to surface and contact cell guidance are of great interest in bio-applications especially on nano- and micro scale features. Recently we showed selective cell responses on Al/Al2O3, bi-phasic nanowires (NWs). In this context, Al/Al2O3 NWs were synthesized by the chemical vapor deposition of (tBuOAIH2)2. Afterwards, linear periodic nano- and micro structured NWs were formed using laser interference lithography (LIL) technique to study the contact guidance of neurons from rat dorsal root ganglion (DRG), human umbilical vein smooth muscle cells (HUVSMC), human umbilical vein endothelial cells (HUVEC) and human osteoblast (HOB). LIL treatment did not alter surface chemistry of NWs. From our preliminary research LIL patterned NWs lead to alignment of axons contrary to non-patterned NWs. Morphology of HUVSMC changed from poly- to linear shapes and strong alignment was observed while HUVEC and HOB were not affected.