Neuroscience
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Mice with a constitutive or tamoxifen-induced Cre recombinase (Cre) expression are frequently used research tools to allow the conditional deletion of target genes via the Cre-loxP system. Here we analyzed for the first time in a comprehensive and comparative way, whether retinal Cre expression or topical tamoxifen treatment itself would cause structural or functional changes, including changes in the expression profiles of molecular markers, glial reactivity and photoreceptor vulnerability. To this end, we characterized the transgenic α-Cre, Lmop-Cre and the tamoxifen-inducible CAGG-CreER™ mouse lines, all having robust Cre expression in the neuronal retina. ⋯ Furthermore, the influence of Cre recombinase or topical tamoxifen exposure on neuronal vulnerability was studied by using light damage as a model for photoreceptor degeneration. Taken together, neither the expression of Cre, nor topical tamoxifen treatment caused detectable changes in retinal structure and function, the expression profiles of investigated molecular markers, glial reactivity and photoreceptor vulnerability. We conclude that the Cre-loxP system and its induction through tamoxifen is a safe and reliable method to delete desired target genes in the neural retina.
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Neuronal cell apoptosis is an important pathological change in Alzheimer's disease (AD). Hydrogen sulfide (H(2)S) is known to be a novel gaseous signaling molecule and a cytoprotectant in many diseases including AD. However, the molecular mechanism of the antiapoptosis activity of H(2)S in AD is not yet fully understood. ⋯ Interestingly, the antiapoptosis effects of H(2)S were blocked down by specific PI3K/AKT inhibitor wortmannin. In conclusion, these data indicate that H(2)S inhibits Aβ-induced neuronal apoptosis by attenuating mitochondrial translocation of PTEN and that activation of PI3K/AKT signaling pathway plays a critical role in H(2)S-mediated neuronal protection. Our findings provide a novel route into the molecular mechanisms of neuronal apoptosis in AD.
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Cellular differentiation is the process, by which a cell changes from one cell type to another, preferentially to the more specialized one. Calcium fluxes play an important role in this action. Differentiated NG108-15 or PC12 cells serve as models for studying neuronal pathways. ⋯ GYY4137 caused a rapid decrease in type 2 sarco/endoplasmic calcium ATPase (SERCA2) mRNA and protein, which results in lower calcium levels in the endoplasmic reticulum compared to the control, untreated group. The dbcAMP revealed rapid increase in expression of the type 3 IP3 receptor, which participates in a calcium clearance from the endoplasmic reticulum. These results point to the important role of reticular calcium in a NG108-15 cell differentiation.
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The expression of β-site APP-cleaving enzyme 1 (BACE1) is increased in the brain of late-onset sporadic Alzheimer's disease (AD) and oxidative stress may be the potential cause of this event. The phenolic glucoside gastrodin (Gas), a main component of a Chinese herbal medicine Gastrodia elata Blume, has been demonstrated to display antioxidant activity and suppresses BACE1 expression. However, the mechanisms by which Gas suppresses BACE1 expression are not clear. ⋯ Moreover, peptide PKR inhibitor (PRI) and Gas down-regulated BACE1 expression in Tg2576 mice and H2O2-stimulated SH-SY5Y cells by inhibiting activation of PKR and eIF2α. Gas alleviates memory deficits in mice and suppresses BACE1 expression by inhibiting the protein kinase/Eukaryotic initiation factor-2α (PKR/eIF2α) pathway. The research suggested that Gas may develop as an drug candidate in neurodegenerative diseases.
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Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. ⋯ However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC.