Biology subjects

Jantti, H.

Publications and source records attributed to Jantti, H..

3 recordsLinked to original sources

bioRxiv2024

Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state

Aberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear. We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question. We generated iPSCs from six pwMS showing increased microglial activity via translocator protein (TSPO)-PET imaging. We demonstrated that the differentiated iMGL transcriptional profile resembled the microglial signature found in MS lesions. Importantly, compared with healthy controls, MS iMGLs presented cell-autonomous differences in their regulation of inflammation, both in the basal state and following inflammatory lipopolysaccharide challenge. Through transcriptomic profiling, we showed that MS iMGLs display increased expression of genes known to be upregulated in MS microglia. Furthermore, upregulated genes in MS iMGLs were associated with immune receptor activation, antigen presentation, and the complement system, with known MS implications. Finally, functional analyses indicated that the transcriptional changes in MS iMGLs corresponded with alterations in the secretion of inflammatory cytokines and chemokines and increased phagocytosis. Together, our results provide evidence of putative cell-autonomous microglial activation in pwMS and identify transcriptomic and functional changes that recapitulate the phenotypes observed in vivo in microglia from pwMS. These findings indicate that MS disease-specific iPSCs are valuable tools for studying disease-specific microglial activation in vitro and highlight microglia as potential therapeutic targets in MS.

neuroscience↗

bioRxiv2024

Protective variant in PLCgamma2 mitigates Alzheimer's disease associated pathology via enhancing beneficial microglia functions

BackgroundPLC{gamma}2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimers disease. Recently, it was shown to decrease {beta}-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLC{gamma}2-P522R variant in a less aggressive mouse model of AD as well as to assess the underlying mechanisms at the molecular and cellular level using mouse and human microglia models. MethodsThe effects of the protective PLC{gamma}2-P522R variant on microglia activation, AD-related {beta}-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLC{gamma}2-P522R knock-in mice crossbred with APP/PS1 AD model mice. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLC{gamma}2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLC{gamma}2-P522R variant carriers were employed to translate the key findings to human cells. ResultsOur results demonstrate that the PLC{gamma}2-P522R variant reduced brain {beta}-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLC{gamma}2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around {beta}-amyloid plaques, leading to reduced {beta}-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLC{gamma}2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLC{gamma}2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLC{gamma}2-P522R increased mitochondrial respiration in iPSC-derived microglial cells. ConclusionsTogether, these findings suggest that PLC{gamma}2-P522R variant exerts protection against AD-associated {beta}-amyloid and neuronal pathologies via enhancing microglial barrier formation around {beta}-amyloid plaques and suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLC{gamma}2-P522R variant are mediated through an anti-ageing mechanism.

neuroscience↗

bioRxiv2024

C9orf72 repeat expansion-carrying iPSC-microglia from FTD patients show increased phagocytic activity concomitantly with decreased number of autophagosomal-lysosomal vesicles

C9orf72 hexanucleotide repeat expansion (HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The role of microglia in these C9orf72 HRE-associated diseases is understudied. To elucidate effects of C9orf72 HRE on microglia, we have characterized human induced pluripotent stem cell-derived microglia (iMG) from behavioral variant frontotemporal dementia (bvFTD) patients carrying the C9orf72 HRE. C9orf72 HRE iMG were compared to iMG from healthy controls and sporadic bvFTD patients. The phenotypes of iMG were analyzed using bulk RNA sequencing, biochemical and immunofluorescence analyses, and live cell imaging. C9orf72 HRE-carrying iMG showed nuclear RNA foci and poly-GP dipeptide repeat proteins but no decreased C9orf72 mRNA or protein expression. TDP-43 pathology was absent from all bvFTD iMG. As compared to healthy control iMG, quantitative immunofluorescence analyses indicated that all bvFTD iMG had reduced number, size, and intensity of LAMP2-A-positive vesicles. C9orf72 HRE-carrying iMG additionally showed decreased number, size, and intensity of p62/SQSTM1-positive vesicles. These changes were accompanied by increased phagocytic activity of the C9orf72 HRE-carrying iMG. Serum starvation increased phagocytic activity also in the iMG of sporadic bvFTD patients. RNA sequencing revealed that iMG of C9orf72 HRE-carrying bvFTD patients as compared to the iMG of sporadic bvFTD patients showed differential gene expression in pathways related to RNA and protein regulation and mitochondrial metabolism. Our data suggest potential alterations in the autophagosomal/lysosomal pathways in bvFTD patient iMG, which are further reinforced by the C9orf72 HRE and functionally manifest as increased phagocytic activity.

neuroscience↗