Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

Agostini, Alessandra; Ding, Yuchun; Li, Bai; Kendall, David A.; Pardon, Marie‐Christine

doi:10.1016/j.bbi.2019.09.019

Cited by 31 publications

(24 citation statements)

References 172 publications

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“…The phenotype of APP/PS1 +/− mice [B6. C3-Tg (APPswe, PSEN1dE9) 85Dbo/J] were identified by genotyping, and were used at 30 weeks of age (n = 40, 20 males and 20 females; Li et al, 2016;vonderEmbse et al, 2017;Agostini et al, 2020). Mice were kept in a 12:12 light-dark cycle at room temperature 22-25 • C with relative humidity 60-80%, and free access to standard laboratory chow and drinking water.…”

Section: Animalsmentioning

confidence: 99%

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease

Zhang

Pei

Zang

et al. 2020

Front. Aging Neurosci.

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Background: There is a significant gender difference in the incidence and symptoms of Alzheimer's disease (AD), but its mechanisms are not completely understood. Recent studies showed that NLRP1 inflammasome was overexpressed in females under some pathological conditions such as nodular melanoma. Whether NLRP1 signals have a gender difference in AD has not been elucidated. This study was designed to investigate gender difference on the expressions of NLRP1 signals including NLRP1, Capase-1 and IL-1β in the brains of APP/PS1 +/− mice. Methods: Female and male APP/PS1 +/− mice (30-weeks-old) were used in this study. Amyloid-β (Aβ) plaques were stained with Congo red dye and cell apoptosis was detected by TUNEL staining. Expressions of NLRP1, Capase-1 and IL-1β were measured by immunofluorescent staining and Western blotting assay. Results: The numbers of Aβ plaques in cortex and hippocampus and neuronal apoptosis in cortex were 4 and 2-folds in females than males, respectively (P < 0.001). The average size of Aβ plaques in both cortex (females: 3527.11 ± 539.88 µm 2 vs. males: 1920.44 ± 638.49 µm 2) and hippocampus (females: 1931 ± 308.61 µm 2 vs. males: 1038.55 ± 220.40 µm 2) were also larger in females than males (P < 0.01). More interestingly, expressions of NLRP1, Caspase-1, and IL-1β were markedly increased in the cortex of females as compared with males. Conclusions: These findings show that NLRP1 signals are higher in brains of female APP/PS1 +/− mice than males, which may be related to the gender differences of AD.

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Section: Animalsmentioning

confidence: 99%

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease

Zhang

Pei

Zang

et al. 2020

Front. Aging Neurosci.

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“…16 Increasing evidence supports that the pathophysiological demonstrations of LPS exposure can include depression and sepsis, acute liver, kidney, and heart injury, as well as other inflammatory response. [17][18][19][20] Although the mechanisms underlying LPS-induced inflammatory responses have been widely investigated, such as, inflammatory cytokine disturbances, 21 inflammatory cytokine disturbances 7 and genetic variability in toll-like receptor 4 (TLR4)-mediated LPS responses, 22,23 an extensive metabolomic characterization of the response to LPS is still lacking.…”

Section: Discussionmentioning

confidence: 99%

<p>Comprehensive Evaluation of Lipopolysaccharide-Induced Changes in Rats Based on Metabolomics</p>

Geng

Guo

Wang³

et al. 2020

JIR

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Purpose: Substantial evidence indicates that lipopolysaccharide (LPS) exposure can lead to systemic inflammatory response syndrome (SIRS) and multiple organ failure. Previous metabolomic studies have mainly focused on LPS-induced depression or hepatic and renal effects. However, no comprehensive metabolomics-based analysis of the serum, liver, kidney, hippocampus, and heart following exposure to LPS has been undertaken to date. Material and Methods: Male Sprague-Dawley rats were randomly allocated to a control and a LPS-treated group (n=8). LPS for 2 weeks (0.5 mg/kg every other day) was given via intraperitoneal injection. Gas chromatography-mass spectrometry (GC-MS) was used for metabolite determination, while multivariate statistical analysis was performed to identify differentially expressed metabolites between the two groups. Results: Our study revealed that 24, 13, 12, 7, and 12 metabolites were differentially expressed between the LPS treatment group and the control group in the serum, liver, kidney, hippocampus, and heart, respectively. We further identified that these metabolic changes were mainly involved with aminoacyl-tRNA biosynthesis; glutathione metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; arginine biosynthesis; bile acid biosynthesis; and glycerolipid metabolism. Conclusion: We have systematically elucidated the metabolic changes underlying LPSinduced SIRS, thereby providing insight into the mechanisms associated with these alterations.

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“…Food burrowing is a species-specific behavior largely dependent on the integrity of the hippocampus (55), which is suppressed in response to systemic inflammation (56,57) and is sensitive to the progression of tau pathology in hTau mice (49). The protocol was adapted from one previously described (49).…”

Section: Food Burrowingmentioning

confidence: 99%

“…We have previously shown that the food burrowing task is the most sensitive test to assess early behavioral perturbations in hTau mice bred on either an mTau −/− (49) or mTau +/− (48) background, and that this behavior is suppressed 4 h after inoculation with LPS in an APP/PS1 mouse model of AD and their Wt littermates (57). Here, mice were assessed for food burrowing performance prior to being challenged with PBS or LPS, and we found that the severity of the food burrowing deficit in 3 -month-old hTau mice was independent of the mTau genotype [genotype: F (4, 171) = 3.89, p = 0.005; hTau/mTau +/− : p = 0.002 vs. Wt; hTau/mTau −/− : p = 0.02 vs. Wt; Figure 1E].…”

Section: Increased 4r Tau Availability In Htau/mtau +/− Exacerbates Tmentioning

confidence: 99%

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

et al. 2020

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but hTau/mTau +/− exhibited more severe sickness behavior at the 100 µg/kg dose and a milder behavioral and cytokine response than hTau/mTau −/− mice at the 330 µg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau +/− mice, but pS202 levels were selectively reduced at the 100 µg/kg dose in hTau/mTau −/− mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau +/− mice.

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Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer’s disease

Cited by 31 publications

References 172 publications

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease

<p>Comprehensive Evaluation of Lipopolysaccharide-Induced Changes in Rats Based on Metabolomics</p>

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

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