Aβ-induced Alzheimer's Disease Research Articles

Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer's disease

GCSF is an endogenous neuronal hematopoietic factor that displays robust in vitro and in vivo neuroprotective activity. The present study aimed to evaluate the effect of GCSF on Aβ-induced memory loss in an Alzheimer's disease model of rats. A total of 42 male adult Wistar rats weighing 200–250g were used in the study and were divided into 7 experimental groups. Animals were subjected to intracerebroventricular (ICV) injection stereotaxically at day 0 to instill amyloid-β1–42 (Aβ1–42) or PBS (sham operated group) at 10μl (5μl bilaterally). GCSF treatment was given from day 7 to 12 of Aβ injection. On day 21, behavioral tests (short term memory, exploratory behavior and motor coordination) in all groups were evaluated. Biochemical parameters and RNA expression were measured to ensure the efficacy of GCSF. GCSF (35 and 70μg/kg, s.c.) showed statistically significant improvement in memory as compared to control and sham operated groups (p<0.05). Mean time spent in the platform placed quadrant was found to be significantly increased in the GCSF (70μg/kg, s.c.) as compared to GCSF (35μg/kg, s.c.) and GCSF (10μg/kg, s.c.) groups (p<0.001). GCSF (35 and 70μg/kg, s.c.) also improved motor coordination and exploratory behavior significantly as compared to naïve sham operated and GCSF (10μg/kg, s.c.) groups (p<0.05). Improvement in memory by GCSF (35 and 70μg/kg, s.c.) was coupled with marked reduction of lipid peroxidation, acetylcholinesterase levels and a significant increase in antioxidant enzymes as well as total RNA expression in the brain. Additionally, GCSF (35 and 70μg/kg, s.c.) significantly increased progenitor cells (iPSCs) and surface marker CD34+ in the brain and hence induced neurogenesis. The present findings demonstrate an improvement of memory and neurobehavioral function with GCSF in Aβ-induced Alzheimer's disease model in rats.

Inflammatory mediator and β-amyloid (25–35)-induced ceramide generation and iNOS expression are inhibited by vitamin E

To investigate the putative role of β-amyloid peptide (Aβ) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and Aβ peptide on the induction of inducible nitric oxide synthase (iNOS). Aβ(25–35) upregulated the cytokine (TNF-α/IL-1 β)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. Aβ treatment of C6 glial cells (together with LPS and IFN-γ), in addition to inducing iNOS, enhanced the oxidative stress as measured by increased expression of manganese superoxide dismutase and an increase in 2,7′-dichlorofluorescein diacetate fluorescence. We also observed that LPS, IFN-γ, and Aβ(25–35) treatment led to the activation of the sphingomyelin–ceramide (SM-Cer) cascade with an increase in cellular ceramide. Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFκB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Aβ-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy.

Inflammatory mediator and $beta;-amyloid (25?35)-induced ceramide generation and iNOS expression are inhibited by vitamin E

To investigate the putative role of β-amyloid peptide (Aβ) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and Aβ peptide on the induction of inducible nitric oxide synthase (iNOS). Aβ(25–35) upregulated the cytokine (TNF-α/IL-1 β)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. Aβ treatment of C6 glial cells (together with LPS and IFN-γ), in addition to inducing iNOS, enhanced the oxidative stress as measured by increased expression of manganese superoxide dismutase and an increase in 2,7′-dichlorofluorescein diacetate fluorescence. We also observed that LPS, IFN-γ, and Aβ(25–35) treatment led to the activation of the sphingomyelin–ceramide (SM-Cer) cascade with an increase in cellular ceramide. Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFκB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Aβ-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy.