Memory Impairment in Estrogen Receptor α Knockout Mice Through Accumulation of Amyloid-β Peptides.
Ontology highlight
ABSTRACT:
SUBMITTER: Hwang CJ
PROVIDER: S-EPMC4510915 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-β 25-35 (Aβ 25-35) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain Aβ 1-42 levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after Aβ25-35 peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented Aβ 25-35-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.
| S-EPMC3671992 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is a progressive, degenerative, and terminal disease without cure. There is an urgent need for a new strategy to treat AD. The aim of this study was to investigate the effects of intermittent hypoxic treatment (IHT) on cognitive functions in a mouse model of AD and unravel the mechanism of action of IHT.MethodsSix-month-old APPswe/PS1dE9 (APP/PS1) male mice were exposed to hypoxic environment (14.3% O2) 4 h/day for 14 days or 28 days. Cognitive functions were measured by Morris water maze test after either 14 days or 42 days of interval. Thereafter the distribution of amyloid plaque and microglial activation were determined by mouse brain immunohistochemistry, while the amyloid beta (Aβ) and inflammatory cytokines were measured by ELISA and Western Blot. Microarray was used for studying gene expressions in the hippocampus.ResultsIHT for 14 days or 28 days significantly improved the spatial memory ability of the 6-month-old APP/PS1 mice. The memory improvement by 14 days IHT lasted to 14 days, but not to 42 days. The level of Aβ plaques and neurofilament accumulations was reduced markedly after the IHT exposure. IHT reduced the pro-inflammatory cytokines IL-1β, IL-6 levels, and β-secretase cleavage of APP processing which implies reduced Aβ production. Microarray analysis revealed a large number of genes in the hippocampus were significantly altered which are known to be metabolism-regulated genes.ConclusionsThis study provides evidence of the beneficial effect of IHT on the progression of AD by alleviating memory impairment, reducing Aβ accumulation and inflammation in the brain. IHT can be developed as a novel measure to relieve the progression of AD by targeting multiple pathways in the AD pathogenesis.
| S-EPMC8630860 | biostudies-literature
Project description:Alzheimer's disease (AD) and Parkinson's disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of ?-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of A?(1-42) and pGlu-A?(3-42) on the aggregation of ?-synuclein in vitro. The aggregation of human recombinant ?-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of ?-synuclein in the presence of minor concentrations of A?(1-42) and pGlu-A?(3-42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of ?-synuclein and A? in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of ?-synuclein and A? and pGlu-A?, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides ?-synuclein and A? species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.
| S-EPMC7037551 | biostudies-literature
Project description:Our previous study presented evidence that the inflammation-related S100A9 gene is significantly upregulated in the brains of Alzheimer's disease (AD) animal models and human AD patients. In addition, experiments have shown that knockdown of S100A9 expression improves cognition function in AD model mice (Tg2576), and these animals exhibit reduced amyloid plaque burden. In this study, we established a new transgenic animal model of AD by crossbreeding the Tg2576 mouse with the S100A9 knockout (KO) mouse. We observed that S100A9KO/Tg2576 (KO/Tg) mice displayed an increased spatial reference memory in the Morris water maze task and Y-maze task as well as decreased amyloid beta peptide (A?) neuropathology because of reduced levels of A?, C-terminal fragments of amyloid precursor protein (APP-CT) and phosphorylated tau and increased expression of anti-inflammatory IL-10 and also decreased expression of inflammatory IL-6 and tumor neurosis factor (TNF)-? when compared with age-matched S100A9WT/Tg2576 (WT/Tg) mice. Overall, these results suggest that S100A9 is responsible for the neurodegeneration and cognitive deficits in Tg2576 mice. The mechanism of S100A9 is able to coincide with the inflammatory process. These findings indicate that knockout of S100A9 is a potential target for the pharmacological therapy of AD.
| S-EPMC3934881 | biostudies-literature
Project description:Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in alpha-synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.
| S-EPMC59799 | biostudies-literature
Project description:Aimsβ-amyloid (Aβ) aggregation and deposition play a central role in the pathogenic process of Alzheimer's disease (AD). α-Mangostin (α-M), a polyphenolic xanthone, have been shown to dissociate Aβ oligomers. In this study, we further investigated the effect of α-M on Aβ production and its molecular mechanism.MethodsThe Aβ and soluble amyloid precursor protein α (sAPPα) in culture medium of cortical neurons were measured by ELISA. The activities of α-, β-, and γ-secretases were assayed, and the interaction between α-M and β- or γ-secretases was simulated by molecular docking.Resultsα-M significantly decreased Aβ40 and Aβ42 production. α-M did not affect the expression of enzymes involved in nonamyloidogenic and amyloidogenic pathways, but significantly decreased the activities of β-secretase and likely γ-secretase with IC50 13.22 nmol·L-1 and 16.98 nmol·L-1 , respectively. Molecular docking demonstrated that α-M interacted with β-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 to interfere with their active sites.ConclusionsOur data demonstrate that α-M decreases Aβ production through inhibiting activities of β-secretase and likely γ-secretase in the amyloidogenic pathway. The current data together with previous study indicated that α-M could be a novel neuroprotective agent through intervention of multiple pathological processes of AD.
| S-EPMC6492755 | biostudies-literature
Project description:BackgroundCrocetin, an agent derived from saffron, has multiple pharmacological properties, such as neuroprotective, anti-oxidant, and anti-inflammatory actions. These properties might benefit the treatment of Alzheimer's disease (AD). In the present study, we tested whether crocetin attenuates inflammation and amyloid-β (Aβ) accumulation in APPsw transgenic mice, AD mouse models. Cell viability and the levels of Aβ40 and Aβ42 in HeLa cells stably transfected with Swedish mutant APP751 were evaluated. Mice with Swedish mutant APP751 transgene were used as transgenic mouse models of AD, and were orally administrated with crocetin. Aβ protein and inflammatory cytokines were measured with ELISA. NF-κB and P53 were measured with western blot assay. Learning and memory were analyzed with Morris water maze and novel object recognition tests.ResultsCrocetin significantly reduced Aβ40 and Aβ42 secretion in Hela cells without effecting cell viability. In AD transgenic mice, crocetin significantly reduced the pro-inflammatory cytokines and enhanced anti-inflammatory cytokine in plasma, suppressed NF-κB activation and P53 expression in the hippocampus, decreased Aβ in various brain areas, and improved learning and memory deficits.ConclusionCrocetin improves Aβ accumulation-induced learning and memory deficit in AD transgenic mice, probably due to its anti-inflammatory and anti-apoptotic functions.
| S-EPMC6208089 | biostudies-literature
Project description:There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.
| S-EPMC5272806 | biostudies-literature
Project description:An abundant presynaptic protein, alpha-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of alpha-synuclein, possibly because alpha-synuclein is redundant with the very similar beta-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack alpha- and/or beta-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by approximately 20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
| S-EPMC522043 | biostudies-literature
Project description:Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain.
| S-EPMC7012599 | biostudies-literature