Biology subjects

Grabert, K.

Publications and source records attributed to Grabert, K..

3 recordsLinked to original sources

bioRxiv2022

The MHC class II transactivator affects local and systemic immune responses in an α-synuclein seeded rat model for Parkinson's disease

BACKGROUNDParkinsons disease (PD) is characterized by alpha-synuclein (-Syn) pathology, neurodegeneration and neuroinflammation. HLA variants associated with PD and -Syn specific circulating CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) is the major regulator of MHCII expression. Reduced Ciita levels significantly increase -Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in -Syn seed-induced rat PD models. OBJECTIVETo characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background (DA) strain. METHODSTo model PD, we combined rAAV-mediated -Syn overexpression in the substantia nigra with striatal injection of -Syn pre-formed fibrils (PFF). Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naive rats, 4- and 8 weeks post rAAV injection. RESULTSFlow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response peaked at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells peaked at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to -Syn and only subtle Ciita- and/or -Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. CONCLUSIONSThese results suggest that Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, and indicate that mild immunomodulatory therapies could have therapeutic effects in PD.

neuroscience↗

bioRxiv2021

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant-negative impact on CSF1R signaling.

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout; with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+ mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein which expands tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborization were reduced in the Csf1rE631K/+ mice as in ALSP patients. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that disease-associated CSF1R mutations encode dominant negative repressors of CSF1R signaling. We speculate that leukoencephalopathy associated with human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Summary StatementThis study describes the effect of a human disease-associated mutation in the mouse CSF1R gene on postnatal development and growth factor responsiveness of cells of the macrophage lineage.

developmental biology↗

bioRxiv2021

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 +microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

neuroscience↗