Journal of Alzheimer's disease : JAD
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Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. ⋯ The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.
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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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Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. ⋯ But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.