2020
DOI: 10.1186/s12974-020-01996-x
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Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Abstract: Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mi… Show more

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Cited by 22 publications
(19 citation statements)
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“…As long as such causative therapies are not established, we consider macrophage targeting as an alternative approach to mitigate disease outcome (Klein et al, 2015; Klein & Martini, 2016). However, the simultaneous, inevitable depletion of microglial cells upon CSF‐1R inhibition has to be critically considered (Berve et al, 2020; Elmore et al, 2014; Elmore et al, 2018; Groh et al, 2019; Lei et al, 2020; Priller & Prinz, 2019; Spangenberg et al, 2019), particularly due to the multiple immunological and neurobiological functions of these cells (Prinz et al, 2021). Another caveat is the need for an early onset of treatment in CMT1A models that certainly makes the translation to clinics problematic.…”
Section: Discussionmentioning
confidence: 99%
“…As long as such causative therapies are not established, we consider macrophage targeting as an alternative approach to mitigate disease outcome (Klein et al, 2015; Klein & Martini, 2016). However, the simultaneous, inevitable depletion of microglial cells upon CSF‐1R inhibition has to be critically considered (Berve et al, 2020; Elmore et al, 2014; Elmore et al, 2018; Groh et al, 2019; Lei et al, 2020; Priller & Prinz, 2019; Spangenberg et al, 2019), particularly due to the multiple immunological and neurobiological functions of these cells (Prinz et al, 2021). Another caveat is the need for an early onset of treatment in CMT1A models that certainly makes the translation to clinics problematic.…”
Section: Discussionmentioning
confidence: 99%
“…Mice of either sex were analysed, since we previously did not detect prominent sex-related differences in untreated Ppt1 − / − mice using the here described readout parameters. 12 Genotypes were determined by conventional PCR using isolated DNA from ear punch biopsies following previously published protocols. 5 In some experiments in which we aimed to genetically inactivate adaptive immune reactions in the CLN1 models, Ppt1- deficient ( Ppt1 − / − ) mice were crossbred with Rag1 -deficient ( Rag1 − / − ) mice 13 according to previously published protocols.…”
Section: Methodsmentioning
confidence: 99%
“…LPS (Sigma-Aldrich) was applied intraperitoneally (0.6 mg/ kg) as described before [23,32]. The preferred application of CSF1R-inhibitor, further referred to as PLX3397 (Plexxikon Inc.), is enteral application with the following variations: mixed into chow, applied via gavage, or mixed into some appealing agent (e.g., corn oil or Nutella®) [33][34][35][36]. Parenteral application has been used before, when enteral application seemed inappropriate [37].…”
Section: Animal Model Of Experimental Sahmentioning
confidence: 99%