scholarly journals Peripheral inflammation increases PKR activation, Tau phosphorylation and amyloid β production in wild-type mice

2013 ◽  
Vol 8 (Suppl 1) ◽  
pp. P32
Author(s):  
François Mouton-Liger ◽  
Anne-Sophie Rebillat ◽  
Clarisse Pace ◽  
Sarah Gourmaud ◽  
Mariko Taga ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Peripheral Inflammation ◽  
Wild Type

scholarly journals Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice

2020 ◽  
Vol 77 (3) ◽  
pp. 1339-1351
Author(s):  
Michela Guglielmotto ◽  
Giusi Manassero ◽  
Valeria Vasciaveo ◽  
Marika Venezia ◽  
Massimo Tabaton ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Conformational Changes ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Paired Helical Filament ◽  
Wild Type ◽  
Aβ Peptides ◽  
Biological Sex ◽  
Nanomolar Concentration ◽  
Estradiol Levels

Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

P2-022: Peripheral inflammation increases PKR, GSK3β, and tau phosphorylation in wild-type mice

2013 ◽  
Vol 9 ◽  
pp. P352-P352
Author(s):  
Anne-Sophie Carret-Rebillat ◽  
François Mouton-Liger ◽  
Clarisse Pace ◽  
Sarah Gourmaud ◽  
Mariko TAGA ◽  
...  
Keyword(s):  
Tau Phosphorylation ◽  
Peripheral Inflammation ◽  
Wild Type

scholarly journals Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

2020 ◽  
Author(s):  
Mickael Audrain ◽  
Jean-Vianney Haure-Mirande ◽  
Justyna Mleczko ◽  
Minghui Wang ◽  
Jennifer K. Griffin ◽  
...  
Keyword(s):  
Late Onset ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Amyloid Burden ◽  
Wild Type ◽  
Sporadic Alzheimer’S Disease ◽  
Stab Injury ◽  
Microglial Phenotype ◽  
Important Regulator

ABSTRACTMicroglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer’s disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgfβ and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-β (Aβ) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

scholarly journals A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Junkai Hu ◽  
Stanley Li Lin ◽  
Melitta Schachner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

2021 ◽  
pp. 0271678X2110395
Author(s):  
Emily C Peters ◽  
Michael T Gee ◽  
Lukas N Pawlowski ◽  
Allison M Kath ◽  
Felipe D Polk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Arteries ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Pial Arteries ◽  
Aspartate Receptor ◽  
Model Of Alzheimer’S Disease ◽  
Intracellular Ca ◽  
Cerebral Amyloid

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid- β(1-40) accumulates around blood vessels. In neurons, amyloid- β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid- β(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR ( NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid- β(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid- β(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid- β(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid- β(1-40) and impaired in 5x-FAD mice.

scholarly journals Cerebral artery dilation during transient ischemia is impaired by amyloid β deposition around the cerebral artery in Alzheimer’s disease model mice

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
Nobuhiro Watanabe ◽  
Yoshihiro Noda ◽  
Taeko Nemoto ◽  
Kaori Iimura ◽  
Takahiko Shimizu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Artery ◽  
Disease Model ◽  
Amyloid Β ◽  
Wild Type ◽  
Transient Ischemia ◽  
Basal Diameter ◽  
Two Photon Microscopy ◽  
Pial Artery

AbstractTransient ischemia is an exacerbation factor of Alzheimer’s disease (AD). We aimed to examine the influence of amyloid β (Aβ) deposition around the cerebral (pial) artery in terms of diameter changes in the cerebral artery during transient ischemia in AD model mice (APPNL-G-F) under urethane anesthesia. Cerebral vasculature and Aβ deposition were examined using two-photon microscopy. Cerebral ischemia was induced by transient occlusion of the unilateral common carotid artery. The diameter of the pial artery was quantitatively measured. In wild-type mice, the diameter of arteries increased during occlusion and returned to their basal diameter after re-opening. In AD model mice, the artery response during occlusion differed depending on Aβ deposition sites. Arterial diameter changes at non-Aβ deposition site were similar to those in wild-type mice, whereas they were significantly smaller at Aβ deposition site. The results suggest that cerebral artery changes during ischemia are impaired by Aβ deposition.

The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice

2006 ◽  
Vol 96 (2) ◽  
pp. 533-540 ◽  
Author(s):  
Masashi Asai ◽  
Chinatsu Hattori ◽  
Nobuhisa Iwata ◽  
Takaomi C. Saido ◽  
Noboru Sasagawa ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
The Novel ◽  
Wild Type ◽  
Secretase Inhibitor

Chronic consumption ofAnnona muricatajuice triggers and aggravates cerebral tau phosphorylation in wild-type andMAPTtransgenic mice

2016 ◽  
Vol 139 (4) ◽  
pp. 624-639 ◽  
Author(s):  
Robert Rottscholl ◽  
Marlen Haegele ◽  
Britta Jainsch ◽  
Hong Xu ◽  
Gesine Respondek ◽  
...  
Keyword(s):  
Tau Phosphorylation ◽  
Wild Type

scholarly journals High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice

2019 ◽  
Vol 149 (12) ◽  
pp. 2247-2254 ◽  
Author(s):  
Min Chen ◽  
Jiashuo Zheng ◽  
Guohao Liu ◽  
Chong Zeng ◽  
En Xu ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Transgenic Mice ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Amyloid Β ◽  
Dietary Iron ◽  
Wild Type ◽  
Brain Iron ◽  
Sod Activity ◽  
The Impact

ABSTRACT Background Brain iron deposition is a feature of Alzheimer disease and may contribute to its development. However, the relative contribution of dietary iron remains unclear. Objectives We investigated the impact of high dietary iron on brain pathological changes and cognitive function in adult wild-type (WT) mice and amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice. Methods Male WT mice and APP/PS1 mice aged 10 wk were fed either a control diet (66 mg Fe/kg) (WT-Ctrl and APP/PS1-Ctrl) or a high iron diet (14 g Fe/kg) (WT-High Fe and APP/PS1-High Fe) for 20 wk. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Brain iron staining and amyloid-β (Aβ) immunostaining were performed. Protein expressions in the hippocampus were determined by immunoblotting. Superoxide dismutase (SOD) activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system. Results In the hippocampus, APP/PS1-High Fe mice had significantly higher iron concentration (2.5-fold) and ferritin (2.0-fold) than APP/PS1-Ctrl mice (P < 0.001), and WT-High Fe mice had significantly higher ferritin (2.0-fold) than WT-Ctrl mice (P < 0.001). Interestingly, APP/PS1 mice had significantly higher iron concentration (2–3-fold) and ferritin (2–2.5-fold) than WT mice fed either diet (P < 0.001). Histological analysis indicated that iron accumulated in the hippocampal dentate gyrus region in APP/PS1 mice, consistent with the pattern of Aβ deposition. For both mouse strains, iron treatment induced Aβ and phospho-τ expression (1.5–3-fold) in the hippocampus, but had little impact on oxidative stress and cognitive function. Furthermore, APP/PS1 mice had significantly lower SOD activity and higher malondialdehyde concentration than WT mice in the hippocampus (P < 0.0001), paralleled by apparent cognitive dysfunction. Conclusions Dietary iron overload induces iron disorder and Aβ and phospho-τ expression in the hippocampus of adult WT and APP/PS1 transgenic mice.

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