TY  - JOUR
AU  - Frolov, Aleksej
AU  - Huang, Hao
AU  - Schütz, Dagmar
AU  - Köhne, Maren Christin
AU  - Blank-Stein, Nelli
AU  - Osei-Sarpong, Collins
AU  - Büttner, Maren
AU  - Elmzzahi, Tarek
AU  - Khundadze, Mukhran
AU  - Zahid, Marina
AU  - Reuter, Michael
AU  - Becker, Matthias
AU  - De Domenico, Elena
AU  - Bonaguro, Lorenzo
AU  - Kallies, Axel
AU  - Morrison, Helen
AU  - Hübner, Christian A
AU  - Händler, Kristian
AU  - Stumm, Ralf
AU  - Mass, Elvira
AU  - Beyer, Marc D
TI  - Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.
JO  - Journal of experimental medicine
VL  - 222
IS  - 7
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DZNE-2025-00556
SP  - e20232357
PY  - 2025
AB  - In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.
KW  - Animals
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - CD8-Positive T-Lymphocytes: pathology
KW  - Microglia: immunology
KW  - Microglia: pathology
KW  - Disease Models, Animal
KW  - Mice
KW  - Neurons: pathology
KW  - Neurons: immunology
KW  - Mice, Knockout
KW  - Lymphocyte Activation: immunology
KW  - Spastic Paraplegia, Hereditary: immunology
KW  - Spastic Paraplegia, Hereditary: pathology
KW  - Mice, Inbred C57BL
LB  - PUB:(DE-HGF)16
C6  - pmid:40266307
DO  - DOI:10.1084/jem.20232357
UR  - https://pub.dzne.de/record/278061
ER  -