Dataset Information

The effect of chronic inflammation on molecular pathways of long-term potentiation in an APP/PS1 mouse model of Alzheimer Disease

ABSTRACT: Alzheimer Disease (AD) is the most common cause of dementia and neuroinflammation, initiated by systemic bacterial infection, is believed to contribute significantly to its pathogenesis. Lipopolysaccharide (LPS) is an endotoxin, which stimulates inflammatory reactions by increasing the levels of pro-inflammatory cytokines through binding to Toll like receptor-4 (TLR-4) and CD14, in an NF-κΒ-dependent fashion. These receptors are expressed in the circumventricular organs, choroid plexus and leptomeninges as well as on microglia cells, thereby providing an entry for an innate immune reaction to spread through the cerebral tissue. Here, 9 months old APP695/PS1ΔE9 (APP/PS1) double transgenic mice and wild type littermates were treated with weekly intraperitoneal injections of LPS or PBS over 13 weeks to evaluate the effect of repeated infections on the innate immune response of the hippocampal proteome. The effect on the proteome was evaluated using a quantitative iTRAQ 8-plex proteomics approach, with 3D-LC-MS/MS to gain a deep coverage of the hippocampal proteome. Furthermore, the effect of long-term inflammation on amyloid beta (Aβ) protein level was evaluated using stereological plaque load estimation followed by investigation of protein levels of Aβ40 and Aβ42 by Mesoscale. An effect of infection on proteins involved in long-term potentiation was observed, including p-MAPK, p-CREB and phosphorylation motifs of PKA and 14-3-3. Furthermore the complement system, redox reactions and the activation of retinoid receptors were found significantly changed in APP/PS1 mice infected with LPS. This study provides new insight into the effect of bacterial infections in the development of AD.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Stefan J. Kempf

LAB HEAD: Martin R. Larsen

PROVIDER: PXD005785 | Pride | 2018-11-21

REPOSITORIES: Pride

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Publications

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1ΔE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer's Disease.

Thygesen Camilla C Ilkjær Laura L Kempf Stefan J SJ Hemdrup Anne Louise AL von Linstow Christian Ulrich CU Babcock Alicia A AA Darvesh Sultan S Larsen Martin R MR Finsen Bente B

Frontiers in cellular neuroscience 20181106

Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer's disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9</ ...[more]

PMID: 30459560

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Project description:Background Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of knocking down microglial iron import gene, Slc11a2, on AD-related cognitive decline and microglial transcriptional phenotype. Methods In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+ or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. Results DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in genes Enpp2, Ttr, and iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers related to disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in female microglia and cognitive deficits in Slc11a2KD APP/PS1 mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

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Dataset Information

The effect of chronic inflammation on molecular pathways of long-term potentiation in an APP/PS1 mouse model of Alzheimer Disease

Dataset's files

Publications

Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APP<sub>SWE</sub>/PS1<sub>ΔE9</sub> Transgenic Mice Implicate Cathepsin Z in Alzheimer's Disease.

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