Characterization of Lipopolysaccharide Effects on LRRK2 Signaling in RAW Macrophages.

Dysfunction of the immune system and mitochondrial metabolism has been associated with Parkinson's disease (PD) pathology. Mutations and increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) are linked to both idiopathic and familial PD. However, the function of LRRK2 in the immune cells under inflammatory conditions is contradictory. Our results showed that lipopolysaccharide (LPS) stimulation increased the kinase activity of LRRK2 in parental RAW 264.7 (WT) cells. In addition to this, LRRK2 deletion in LRRK2 KO RAW 264.7 (KO) cells altered cell morphology following LPS stimulation compared to the WT cells, as shown by an increase in the cell impedance as observed by the xCELLigence measurements. LPS stimulation caused an increase in the cellular reactive oxygen species (ROS) levels in both WT and KO cells. However, WT cells displayed a higher ROS level compared to the KO cells. Moreover, LRRK2 deletion led to a reduction in interleukin-6 (IL-6) inflammatory cytokine and cyclooxygenase-2 (COX-2) expression and an increase in lactate production after LPS stimulation compared to the WT cells. These data illustrate that LRRK2 has an effect on inflammatory processes in RAW macrophages upon LPS stimulation.

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression.

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

Aging, sex, metabolic and life experience factors: Contributions to neuro-inflammaging in Alzheimer's disease research.

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook.