TY  - JOUR
AU  - Hartmann, Christiane
AU  - Haß, Christina
AU  - Knobloch, Muriel
AU  - Barrantes, Israel
AU  - Fumagalli, Laura
AU  - Premereur, Jessie
AU  - Markert, Franz
AU  - Peters, Maite
AU  - Koromila, Georgia
AU  - Hartmann, Alexander
AU  - Jäger, Kathrin
AU  - Abel, Jette
AU  - Mancuso, Renzo
AU  - Storch, Alexander
AU  - Walter, Michael
AU  - Fuellen, Georg
AU  - Hermann, Andreas
TI  - Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.
JO  - Aging cell
VL  - 24
IS  - 11
SN  - 1474-9718
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2025-01267
SP  - e70232
PY  - 2025
AB  - Microglia, the brain's resident immune cells, are crucial for maintaining healthy brain homeostasis. However, as the brain ages, microglia can shift from a neuroprotective to a neurotoxic phenotype, contributing to chronic inflammation and promoting neurodegenerative processes. Despite the importance of understanding microglial aging, there are currently few human in vitro models to study these processes. To address this gap, we have developed a model in which human microglia undergo accelerated aging through inducible progerin expression. HMC3-Progerin cells display key age-related markers such as activation of the senescence-associated secretory phenotype (SASP) as well as an increase in DNA damage. These prematurely aged HMC3 cells show a reduced response to LPS activation, exhibit impairments in essential microglial functions including decreased migration and phagocytosis as well as transcriptomic alterations including a shift observed in aging and neurodegeneration. Additionally, we observed an impaired stress response and a defect in nucleocytoplasmic transport, especially affecting the amyotrophic lateral sclerosis (ALS) associated protein FUS. This suggests that microglia play a contributory role in driving neurodegenerative processes in the aging brain. Our microglia aging model offers a valuable tool for exploring how aged microglia affect brain function, enhancing our understanding of their role in brain aging.
KW  - Humans
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - RNA-Binding Protein FUS: metabolism
KW  - Cellular Senescence
KW  - Active Transport, Cell Nucleus
KW  - Stress, Physiological
KW  - Phagocytosis
KW  - FUS (Other)
KW  - aging (Other)
KW  - aging clock (Other)
KW  - amyotrophic lateral sclerosis (Other)
KW  - microglia (Other)
KW  - nucleocytoplasmic shuttling (Other)
KW  - progerin (Other)
KW  - senolytics (Other)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40970514
C2  - pmc:PMC12610945
DO  - DOI:10.1111/acel.70232
UR  - https://pub.dzne.de/record/282297
ER  -