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