Biology subjects

Hirbec, H. E.

Publications and source records attributed to Hirbec, H. E..

2 recordsLinked to original sources

bioRxiv2025

Increased white matter microglial reaction and perivascular macrophages in the aging microcebe primate

As populations age, the incidence of neurodegenerative disorders is rising. Early age-related neuropathological changes are the breeding ground for the development of these disorders. Microglia are the resident macrophages of the central nervous system. They play crucial roles in maintaining brain homeostasis, yet their age-related changes remain not fully understood. While age-related microglia changes have been strongly characterized in rodents, studies in non-human primates are scarce. The microcebe primate (mouse lemur (Microcebus murinus)) is widely used as a model for cerebral aging and to investigate age-related neurodegenerative processes. HLA-DR is a major histocompatibility class II cell surface receptor which presents antigens to cells of the immune response. It is a major marker of microglia reaction. In this study, we explored microglia in the whole brains of middle-aged and old microcebes using HLA-DR immunolabeling. We analyzed microglial morphology and quantified HLA-DR+ cell density and protein expression. A wide range of microglial morphologies was observed in the white matter, including thin processes microglia, "rod-like" elongated and polarized shape, hypertrophic, and amoeboid microglia. Aging was associated with increased HLA-DR+ microglial expression in the white matter while very few HLA-DR+ microglia were observed in the parenchyma of cortical gray matter regions. A second finding was the higher number of HLA-DR+ perivascular macrophages in old animals. This study in a primate outlines that, in the absence of neurodegenerative processes, the most prominent signs of age-related microglia/macrophage changes are region-specific and concern white matter and perivascular regions. This emphasizes the need to target these regions to prevent cerebral aging. Main PointsO_LIHLA-DR+ microglia in Microcebus murinus primate show diverse morphologies and increase with age in white matter. C_LIO_LIHLA-DR+ perivascular macrophage load increase in aged animals. C_LI Table of Contents Image (TOCI) O_FIG O_LINKSMALLFIG WIDTH=167 HEIGHT=200 SRC="FIGDIR/small/645519v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@edb574org.highwire.dtl.DTLVardef@23f606org.highwire.dtl.DTLVardef@ed2e0borg.highwire.dtl.DTLVardef@169f059_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Neuroprotection by chronic administration of Fluoroethylnormemantine (FENM) in mouse models of Alzheimer's disease

BackgroundFluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-{beta}[25-35] peptide (A{beta}25-35)-induced neurotoxicity in mice, a pharmacological model of Alzheimers disease (AD) with high predictive value for drug discovery. Here, as drug infusion is likely to better reflect drug bioavailability due to the interspecies pharmacokinetics variation, we analyzed the efficacy of FENM after chronic subcutaneous (SC) infusion, in comparison with IP injections in two AD mouse models, A{beta}25-35 -injected mice and the transgenic APP /PSEN1{partial}E9 (APP/PS1) line. MethodsIn A{beta}25-35-treated mice, FENM was infused at 0.03-0.3 mg/kg/day during one week after A{beta}25-35 injection. For comparison, FENM and MEM were administered IP daily at 0.03-0.3 mg/kg. In 10-month-old APP/PS1 mice, FENM was administered during four weeks by daily IP injections at 0.3 mg/kg or chronic SC infusion at 0.1 mg/kg/day. Memory deficits, spatial working memory and recognition memory, were analysed. Markers of neuroinflammation, apoptosis, oxidative stress, and amyloid burden in APP/PS1 mice, were quantified. Markers of synaptic plasticity such as PSD-95 and GluN2A/B/D subunits expression in hippocampus homogenates or synaptosomes were quantified in A{beta}25-35-treated mice and synaptic long-term potentiation (LTP) in hippocampal slices was analysed in APP/PS1 mice. ResultsDeficits in spontaneous alternation and object recognition in A{beta}25-35 mice were prevented by infused FENM at all doses tested. Similar effects were observed with the daily FENM or MEM treatments. Animals infused with 0.1 mg/kg/day FENM showed prevention of A{beta}25-35-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored A{beta}25-35-induced alterations in synaptosomal PSD-95, GluN2A and P-GluN2B levels. GluN2D levels were unchanged whatever the treatment. In APP/PS1 mice, FENM infused or administered IP alleviated spontaneous alternation deficits, neuroinflammation, increases in A{beta}1-40/A{beta}1-42 and hippocampal LTP alteration. ConclusionThese data confirmed the neuroprotective potential of FENM in the pharmacological A{beta}25-35 and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.

pharmacology and toxicology↗