Biology subjects

Klaestrup, I. H.

Publications and source records attributed to Klaestrup, I. H..

4 recordsLinked to original sources

bioRxiv2025

Lack of functional STING modulates immunity but does not protect dopaminergic neurons in the alpha-synuclein preformed fibrils Parkinson's Disease mouse model

Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (-syn) pathology in Parkinsons disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 {micro}g of murine pre-formed fibrils (PFFs) of -syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STINGgt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-months post-injection. STINGgt/gt mice showed more motor changes associated with PFF injection than WT mice. STINGgt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1b, and TREM2. However, the lack of STING did not induce changes in the extent of -syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the -syn induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amylogenic proteins such as -syn that can contribute to symptomatic changes.

neuroscience↗

bioRxiv2024

Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus 1 CNS infection

Herpes Simplex Virus 1 (HSV-1) is a common human neurotropic virus with the majority of adults harboring latent-recurrent infections. In rare cases, HSV-1 infection can access the central nervous system through the neuronal route and develop into life-threatening encephalitis. Here, we used a mouse model for HSV-1 infection to describe the transcriptomic profile of the infected brain stem at the single-cell level and with temporal resolution. Among resident brain cells, microglia increased in proportion during the course of infection, while astrocytes, pericytes, and endothelial cell levels decrease. At the levels of peripheral immune cells, we found notably monocytes to strongly influx the infected brain. Large dynamic changes were found in the abundance of subpopulations of the different cell types following virus infection. For instance, we identify one subpopulation of microglia exhibiting very high type I interferon and chemokine expression early during infection. This population was also enriched for viral transcripts, suggesting localization at foci of infection, and orchestrating recruitment of other immune cells. In contrast, for the infiltrating monocytes, we identified a larger panel of unique subpopulations with antiviral and inflammatory phenotypes, and found not all of these being highly positive for viral transcripts, thus indicating monocyte activities beyond the infected brain areas. Finally, investigation of endothelial cell cross-talk with other cell types revealed that cytokines derived from microglia and monocyte, but also T cells, contribute to disturbance of the blood brain barrier. Our work thus reveals for the first time the complex nature of the cellular response in the virus-infected brain, which seeks to eliminate infection but can also prime for pathological changes.

immunology↗

bioRxiv2022

Sex-dimorphic neuroprotective effect of CD163 in an alpha-synuclein mouse model Of Parkinson's disease

Alpha-synuclein (-syn) aggregation and immune activation represent hallmark pathological events in Parkinsons disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in the PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine -syn pre-formed fibrils (PFF) in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to -syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and -syn pathology, which ultimately led to dopaminergic neurodegeneration of greater magnitude. These findings support a novel, sex-dimorphic neuroprotective role for CD163 during -syn-induced neurodegeneration.

neuroscience↗

bioRxiv2021

Enhanced Production of Mesencephalic Dopaminergic Neurons from Lineage-Restricted Human Undifferentiated Stem Cells

The differentiation of human pluripotent stem cells (hPSCs) into mesencephalic dopaminergic (mesDA) neurons requires a precise combination of extrinsic factors that recapitulates the in vivo environment and timing. Current methods are capable of generating authentic mesDA neurons after long-term culture in vitro; however, when mesDA progenitors are transplanted in vivo, the resulting mesDA neurons are only minor components of the graft. This low yield hampers the broad use of these cells in the clinic. In this study, we genetically modified pluripotent stem cells to generate a novel type of stem cells called lineage-restricted undifferentiated stem cells (LR-USCs), which robustly generate mesDA neurons. LR-USCs are prevented from differentiating into a broad range of nondopaminergic cell types by knocking out genes that are critical for the specification of cells of alternate lineages. Specifically, we target transcription factors involved in the production of spinal cord and posterior hindbrain cell types. When LR-USCs are differentiated under caudalizing condition, which normally give rise to hindbrain cell types, a large proportion adopt a midbrain identity and develop into authentic mesDA neurons. We show that the mesDA neurons are electrophysiologically active, and due to their higher purity, are capable of restoring motor behavior eight weeks after transplantation into 6-hydroxydopamine (6-OHDA)-lesioned rats. This novel strategy improves the reliability and scalability of mesDA neuron generation for clinical use.

neuroscience↗