ABSTRACT
Transthyretin (TTR) binds amyloid-beta (Abeta) and prevents Abeta fibril formation in vitro. It was reported that the lack of neurodegeneration in a transgenic mouse model of Alzheimer's disease (AD) (Tg2576 mouse) was associated with increased TTR level in the hippocampus, and that chronic infusion of anti-TTR antibody into the hippocampus of Tg2576 mice led to increased local Abeta deposits, tau hyperphosphorylation and apoptosis. TTR is, therefore, speculated to prevent Abeta pathology in AD. However, a role for TTR in Abeta deposition is not yet known. To investigate the relationship between TTR and Abeta deposition, we generated a mouse line carrying a null mutation at the endogenous TTR locus and the human mutant amyloid precursor protein cDNA responsible for familial AD (Tg2576/TTR(-/-) mouse) by crossing Tg2576 mice with TTR-deficient mice. We asked whether Abeta deposition was accelerated in Tg2576/TTR(-/-) mice relative to the heterozygous mutant Tg2576 (Tg2576/TTR(+/-)) mice. Contrary to our expectations, the degree of total and vascular Abeta burdens in the aged Tg2576/TTR(-/-) mice was significantly reduced relative to the age-matched Tg2576/TTR(+/-) mice. Our experiments present, for the first time, compelling evidence that TTR does not suppress but rather accelerates vascular Abeta deposition in the mouse model of AD.
Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Prealbumin/deficiency , Age Factors , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Blood Vessels/metabolism , Blood Vessels/pathology , Blotting, Western , Brain/metabolism , Brain/pathology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Heterozygote , Hippocampus/metabolism , Hippocampus/pathology , Homozygote , Humans , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peptide Fragments/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Prealbumin/geneticsABSTRACT
The therapeutic use of interferon-alpha (IFN-alpha), a proinflammatory cytokine, is known to cause various neuropsychiatric adverse effects. In particular, depression occurs in 30-45% of patients, frequently interrupting treatment. IFN-alpha-treated animals also show depression-like behaviors. However, mechanisms underlying the depression caused by IFN-alpha remain to be defined. Recently, a decrease in adult hippocampal neurogenesis was revealed as a possible neuropathological mechanism of depression. Therefore, we investigated the effect of subchronic IFN-alpha treatment on neurogenesis in the adult rat dentate gyrus (DG). Immediately after the administration of IFN-alpha for 1 week, a decrease in the number of 5-bromo-deoxyuridine-labeled proliferating cells was observed in the DG; however, no effect was detected on the expression of mature neuronal phenotype in the newly formed cells 3 weeks later. Also, an increase in the level of interleukin-1beta (IL-1beta), a major proinflammatory cytokine, was observed in the hippocampus following the administration of IFN-alpha. Furthermore, coadministration of an IL-1 receptor antagonist completely blocked the IFN-alpha-induced suppression of the cell-proliferative activity in the DG. Our results indicate that IFN-alpha suppresses neurogenesis in the DG, and that IL-1beta plays an essential role in the suppression. The decreased cell proliferation caused by IFN-alpha-induced IL-1beta may be responsible, at least in part, for IFN-alpha-induced depression.
Subject(s)
Cell Proliferation/drug effects , Dentate Gyrus/drug effects , Interferon-alpha/adverse effects , Interleukin-1beta/agonists , Neurons/drug effects , Animals , Bromodeoxyuridine , Cell Division/drug effects , Cell Division/immunology , Dentate Gyrus/immunology , Dentate Gyrus/physiopathology , Depressive Disorder/chemically induced , Depressive Disorder/immunology , Depressive Disorder/physiopathology , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Immunologic Factors/adverse effects , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Male , Neurons/immunology , Rats , Rats, Wistar , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/immunologyABSTRACT
In aged rats, although learning and memory impairment is prominent, both the number of granular cells and the degree of neuronal progenitor proliferation in the hippocampus are known to be preserved. We examined the association between the survival of newly generated neurons in the hippocampus and the learning ability in aged rats. By using BrdU, a cell proliferation marker to determine neurogenesis and contextual fear conditioning to determine learning ability, we found that in aged rats, along with memory impairment, the survival of both the proliferated cells at baseline and those enhanced by contextual fear conditioning decreased remarkably. These results suggest that the integration of newly generated neurons into hippocampal circuitry is decreased with aging, this phenomenon may, in part, explain the decline in learning and memory in aged rats.
Subject(s)
Aging , Cell Proliferation , Cell Survival , Hippocampus/cytology , Memory , Spatial Behavior , Animals , Bromodeoxyuridine/metabolism , Conditioning, Psychological , Fear , Hippocampus/metabolism , Immunohistochemistry , Male , RatsABSTRACT
In the early process of long-term memory formation, cyclic AMP response element-binding protein (CREB), a transcription factor on which multiple signal transduction pathways converge, has been implicated. We examined whether the age difference in the performance of contextual fear conditioning (CFC) is associated with a change in activation of CREB in the hippocampus which is an important neural structure for long-term memory. The activation of CREB in the hippocampus in young (15 weeks old) and old (120 weeks old) male rats was determined immunohistochemically with an antibody that specifically recognizes the phosphorylated form of CREB (pCREB). Young rats exhibited better performance than old rats with respect to the freezing time in CFC. Phosphorylation of CREB as revealed by the ratio of the pCREB-immunoreactive cell number to the CREB-immunoreactive cell number was increased in the CA1 region, but not in other hippocampal regions following training for CFC. The close relationship between behavioral performance and CREB phosphorylation in the CA1 region suggests that hippocampal CREB is involved in age-related decline of learning and memory.
Subject(s)
Aging/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Hippocampus/metabolism , Memory/physiology , Analysis of Variance , Animals , Behavior, Animal , Cell Count/methods , Conditioning, Classical/physiology , Electroshock/methods , Fear , Immunohistochemistry/methods , Male , Phosphorylation , Rats , Time FactorsABSTRACT
Panax Ginseng is a commonly used galenical known to have an enhancing effect on learning. Neurogenesis in the hippocampus has been shown to be necessary for hippocampus/amygdala-dependent learning tasks. To investigate the role of Ginseng in neurogenesis and learning of rats, we administered both Ginseng and BrdU for five consecutive days. As a result, Ginseng increased the number of BrdU-positive cells in the dentate gyrus in a dose-dependent manner. Further, we administered one dose of BrdU after Ginseng treatment for five consecutive days, and the number of BrdU-positive cells did not increase significantly. However, when one dose of BrdU was given 1 day before the following five consecutive days of Ginseng treatment, the number of BrdU-positive cells markedly increased in the hippocampus. Therefore, it is likely that Ginseng enhances not proliferation but survival of newly generated neurons in the hippocampus. Second, we administered both Ginseng and BrdU to rats for five consecutive days. One day after the last Ginseng and BrdU co-administration, contextual fear conditioning (CFC) was conducted. Ginseng in a dose-dependent manner increased the % freezing time and the number of BrdU-positive cells in the dentate gyrus of rats that received CFC. Thus, an increase in CFC-related neurogenesis may be one mechanism of Ginseng's properties to enhance learning ability.
