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Effect of systemic, low-dose LPS treatment on brain proteome of PFF-inoculated mice

ABSTRACT: Brain aggregates of α-synuclein (α-syn) characterizes a group of diseases defined as synucleinopathies. Recent studies implicate neuroinflammation as one of the central pathogenic mechanisms. However, how inflammation is linked to the α-syn pathology is still unknown. We wanted to address this by a ‘double-hit’ approach. Three weeks after intra-striatal injections of human α-syn pre-formed fibrils (PFF), mice were subjected for 3 weeks to repeated intraperitoneal injections of low concentrations (1 mg/ml) of lipopolysaccharide (LPS), a component of gram-negative bacteria. Histological analysis confirmed brain propagation of α-syn aggregation in PFF-injected mice independent of LPS-injections. No motor dysfunction was observed at this stage as measured in the pole test. Spleen immune cell profiling and multiplex cytokine analysis confirmed LPS-induced changes in T- and B-cells populations, monocytes, and neutrophils, and increased brain TNF-α, IL-β, IL-10 and KC/GRO levels. LC-MS/MS analysis in the forebrain area and subsequent downstream ReactomeGSA pathway analysis revealed that PFF-injections induced alterations in mitochondrial metabolism and neurotransmitter signaling. Systemic inflammation resulted in an overrepresentation of complement and coagulation pathways and upregulation of integrin and B cell receptor signaling in the PFF-injected mice.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Anne-Line Laursen

LAB HEAD: Susana Aznar

PROVIDER: PXD039193 | Pride | 2024-09-05

REPOSITORIES: Pride

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			Action	DRS
	20220417_RRJ_Bio_LTD_AL_10_01.raw	Raw
	20220417_RRJ_Bio_LTD_AL_10_02_20220508032305.raw	Raw
	20220417_RRJ_Bio_LTD_AL_10_03.raw	Raw
	20220417_RRJ_Bio_LTD_AL_11_01.raw	Raw
	20220417_RRJ_Bio_LTD_AL_11_02_20220508114932.raw	Raw

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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

Project description:Kuznetsov2016(II) - α-syn aggregation kinetics in Parkinson's This theoretical model uses 2-step Finke-Watzky (FW) kinetics todescribe the production, misfolding, aggregation, transport and degradation of α-syn that may lead to Parkinson's Disease (PD). Deregulated α-syn degradation is predicted to be crucialfor PD pathogenesis. This model is described in the article: What can trigger the onset of Parkinson's disease - A modeling study based on a compartmental model of α-synuclein transport and aggregation in neurons. Kuznetsov IA, Kuznetsov AV. Math Biosci 2016 Aug; 278: 22-29 Abstract: The aim of this paper is to develop a minimal model describing events leading to the onset of Parkinson's disease (PD). The model accounts for α-synuclein (α-syn) production in the soma, transport toward the synapse, misfolding, and aggregation. The production and aggregation of polymeric α-syn is simulated using a minimalistic 2-step Finke-Watzky model. We utilized the developed model to analyze what changes in a healthy neuron are likely to lead to the onset of α-syn aggregation. We checked the effects of interruption of α-syn transport toward the synapse, entry of misfolded (infectious) α-syn into the somatic and synaptic compartments, increasing the rate of α-syn synthesis in the soma, and failure of α-syn degradation machinery. Our model suggests that failure of α-syn degradation machinery is probably the most likely cause for the onset of α-syn aggregation leading to PD. This model is hosted on BioModels Database and identified by: BIOMD0000000615. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Effect of systemic, low-dose LPS treatment on brain proteome of PFF-inoculated mice

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