Biology subjects

Feuerbach, D.

Publications and source records attributed to Feuerbach, D..

3 recordsLinked to original sources

bioRxiv2021

Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimers disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to A{beta} pathology in a mouse model of Alzheimers disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

neuroscience↗

bioRxiv2020

JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters of in vitro microglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson's disease.

Alpha-7-nicotine-acetylcholine-receptor (7-nAChRs) agonists modulate the cholinergic antiinflammatory pathway to attenuate proinflammatory signals and reduce dopaminergic neuronal cell loss in toxin-induced experimental murine models of Parkinsons disease (PD). The protein -synuclein (Syn) is considered to represent the major pathogenic component in the etiology and progression of sporadic PD. However, no research has been performed to evaluate the effect of 7-nAChR agonists in human Syn mediated models of PD. We, therefore, investigated the effect of the compound JN403, an 7-nAChR specific agonist, in Syn treated in vitro microglia culture and in a human Syn overexpression in vivo mouse model. In primary mouse microglia cells, Syn fragment 61-140 treatment increased the release of nitric oxide (NO), tumor necrosis factor (TNF)- and interleukin (IL)-6, and decreased cell viability. In contrast, 100 nM or 1 M of JN403 co-incubation significantly reduced the level of NO and TNF- release in the microglial cells. For in-vivo testing of JN403, a recombinant adeno-associated viral vector (rAAV)-mediated unilateral intranigral overexpression of human wild-type-Syn (WT-Syn) or of the control protein luciferase (luc) was induced via stereotactic delivery in C57/BL6N mice. Targeted WT-Syn overexpression reduced 20% of the number of tyrosine hydroxylase (TH) positive (+) nigral neurons after 10 weeks. Subcutaneous daily treatment of 30 mg/kg JN403 over 9 weeks starting at postoperative week 1 did not alter the decrease of TH+ neuronal numbers, and microglial density in WT-Syn overexpression mouse model. The reduced density of TH+ striatal terminals in the WT-Syn groups was also not recovered by the JN403 treatment. In summary, JN403, an 7-nAChR specific agonist shows a beneficial effect on ameliorating proinflammatory signals in Syn exposed microglia cells. However, no significant in-vivo treatment effect was found in an intranigral WT-Syn overexpression mouse model of PD.

neuroscience↗

bioRxiv2017

ADAM17 Is The Main Sheddase For The Generation Of Human Triggering Receptor Expressed In Myeloid Cells (hTREM2) Ectodomain And Cleaves TREM2 After Histidine 157

Triggering receptor expressed in myeloid cells (TREM2) is a member of the immunoglobulin superfamily and is expressed in macrophages, dendritic cells, microglia, and osteoclasts. TREM2 plays a role in phagocytosis, regulates release of cytokine, contributes to microglia maintenance, and its ectodomain is shed from the cell surface. Using both pharmacological and genetic approaches we report here that the main protease contributing to the release of TREM2 ectodomain is ADAM17, (a disintegrin and metalloproteinase domain containing protein, also called TACE, TNF converting enzyme) while ADAM10 plays a minor role. Using mutational analysis, we demonstrate that the main cleavage site of the sheddases is located within the stalk region of TREM2 proximal to the plasma membrane. Complementary biochemical experiments reveal that cleavage occurs between histidine 157 and serine 158. Shedding is not altered for the R47H-mutated TREM2 protein that confers an increased risk for the development of Alzheimers disease. O-glycosylation is detected within the stalk region, but distant to the cleavage site. These findings reveal a link between shedding of TREM2 and its regulation during inflammatory conditions or chronic neurodegenerative disease like AD in which activity or expression of sheddases might be altered.

cell biology↗