Biology subjects

Paris, I.

Publications and source records attributed to Paris, I..

4 recordsLinked to original sources

bioRxiv2025

Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques

Anti-amyloid {beta}-peptide (A{beta}) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimers disease. Efficient amyloid plaque clearance has been proven in clinical trials testing anti-A{beta} antibodies, with the impact on cognitive endpoints correlating with the extent of plaque removal. However, treatment is associated with adverse side-effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-A{beta} antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-A{beta} treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with anti-A{beta} antibody from 4-8 months of age. Long-term treatment with anti-A{beta} results in a robust and dose-dependent removal of amyloid plaque pathology, with a higher efficiency for removing diffuse over dense-core plaques. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and -Synuclein, as well as immune cell related proteins. Bulk RNA-seq revealed a dose-dependent decrease in brain-wide disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering receptor of myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around remaining plaques remains high regardless of treatment dose. In addition, microglia surrounding remaining plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen presenting and immune signalling proteins. These findings demonstrate that long-term chronic anti-A{beta} mediated removal of A{beta} leads to a dose dependent decrease in brain-wide microglial DAM activation and neurodegeneration, while microglia at residual plaques display a combined DAM and antigen presenting phenotype that suggests a continued treatment response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/645950v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6d1a49org.highwire.dtl.DTLVardef@d8c14dorg.highwire.dtl.DTLVardef@7ae330org.highwire.dtl.DTLVardef@1d96cc3_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: Schematic overview of the effects of chronic long-term anti-A treatment in APP-SAA mice Schematic was created with BioRender.com C_FIG

neuroscience↗

bioRxiv2024

A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors.

Phagocytosis is an indispensable function of microglia, the brain professional phagocytes. Microglia are particularly efficient phagocytosing cells that undergo programmed cell death (apoptosis) in physiological conditions. However, mounting evidence suggests microglial phagocytosis dysfunction in multiple brain disorders. These observations prompted us to search for phagocytosis modulators (enhancers or inhibitors) with therapeutic potential. We used a bottom-up strategy that consisted on the identification of phagocytosis modulators using phenotypic high throughput screenings (HTSs) in cell culture and validation in organotypic cultures and in vivo. We performed two complementary HTS campagnes: at Achucarro, we used primary cultures of mouse microglia and compounds of the Prestwick Chemical Library; at Roche, we used human iPSC derived macrophage-like cells and a proprietary chemo-genomic library with 2,200 compounds with known mechanism-of-action. Next, we validated the more robust compounds using hippocampal organotypic cultures and identified two hits: trifluoperazine, a dopaminergic and adrenergic antagonist used as an antipsychotic and antineoplastic; and deoxytubercidin, a ribose derivative. Finally, we tested whether these compounds were able to modulate phagocytosis of apoptotic newborn cells in the adult hippocampal neurogenic niche in vivo by administering them into the mouse hippocampus using osmotic minipumps. We confirmed that both trifluoperazine and deoxytubercidin have anti-phagocytic activity in vivo, and validated our bottom-up strategy to identify novel phagocytosis modulators. These results show that chemical libraries with anotated mechanism of action are an starting point for the pharmacological modulation of microglia in drug discovery projects aiming at the therapeutic manipulation of phagocytosis in brain diseases. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/599284v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@13ed994org.highwire.dtl.DTLVardef@13ea710org.highwire.dtl.DTLVardef@4a1c7dorg.highwire.dtl.DTLVardef@1945f00_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral AAV-mediated expression of brain-penetrant progranulin

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD-GRN, namely Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN associated disease pathologies including severe motor function deficits, aberrant TDP-43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel human in vitro model using co-cultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders. One sentence summaryPeripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRN models.

neuroscience↗

bioRxiv2019

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of their intracellular contents. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in mice chronically deficient for two microglial phagocytosis pathways (P2Y12 and MerTK/Axl), but was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of microglial phagocytosis in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia act as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.\n\nGRAPHICAL ABSTRACT

cell biology↗