Journal of Alzheimer's disease : JAD
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Increasing evidence supports that amyloid plaques, comprised of amyloid-β (Aβ), are a key feature of Alzheimer's disease (AD). But the mechanism of Aβ in AD is not yet fully understood. Previous studies have demonstrated that in Aβ-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-κB) is activated. ⋯ These phenomena indicated that FAK is upstream of ERK1/2, p38MAPK, and NF-κB, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-κB. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with IκB kinase. Taken together, our results suggest that FAK activates NF-κB via ERK1/2 and p38MAPK pathways in Aβ(25-35)-induced apoptosis of differentiated PC12 cells.
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The aim of this work was to explore the applicable value of (1)H-MRS evaluation on the treatment of Alzheimer's disease (AD) with neural stem cell (NSC) transplantation by quantitative analysis of metabolite changes in the hippocampal area in AβPP/PS1 transgenic (tg) mice. The tg mice (n = 30) aged 12 months were randomized into two subgroups: One receiving NSCs and the other receiving PBS transplantation in the bilateral hippocampal CA1 region. The wild-type mice (n = 15) were used as the control group. (1)H-MRS was performed before transplantation and 6 weeks after transplantation to measure the change of N-acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), choline (Cho), and creatine (Cr) in the hippocampus. ⋯ Histology showed the number of neurons in the hippocampal CA1 region increased significantly in the NSC group than those in the PBS group (p < 0.05), and the number of astrocytes significantly decreased in the NSC group compared with the PBS group. Ultrastructure showed that the neurons in the NSC group were morphologically normal. In conclusion, (1)H-MRS can display intracranial metabolite changes before and after NSC transplantation in tg mice and has a applicable value in evaluating the therapeutic effect of NSCs on AD.
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The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. ⋯ In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD.
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The output of cortical pyramidal cells reflects the balance between excitatory inputs of cortical and subcortical origin, and inhibitory inputs from distinct populations of cortical GABAergic interneurons, each of which selectively innervate different domains of neuronal pyramidal cells (i.e., dendrites, soma and axon initial segment [AIS]). In Alzheimer's disease (AD), the presence of amyloid-β (Aβ) plaques alters the synaptic input to pyramidal cells in a number of ways. However, the effects of Aβ plaques on the AIS have still not been investigated to date. ⋯ In the AβPP/PS1 transgenic mouse model of AD, we have investigated the effects of Aβ plaques on the morphological and neurochemical features of the AIS, including the cisternal organelle, using immunocytochemistry and confocal microscopy, as well as studying the innervation of the AIS by chandelier cell axon terminals. There is a strong reduction in GABAergic terminals that appose AIS membrane surfaces that are in contact with Aβ plaques, indicating altered inhibitory synapsis at the AIS. Thus, despite a lack of gross structural alterations in the AIS, this decrease in GABAergic innervation may deregulate AIS activity and contribute to the hyperactivity of neurons in contact with Aβ plaques.
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Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe-/- mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. ⋯ The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe-/- mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading.