TY  - JOUR
AU  - Villacampa, Nàdia
AU  - Sarlus, Heela
AU  - Martorell, Paula
AU  - Bhalla, Khushbu
AU  - Gomez-Castro, Sergio
AU  - Vieira-Saecker, Ana
AU  - Slutzkin, Ilya
AU  - Händler, Kristian
AU  - Venegas, Carmen
AU  - McManus, Róisín
AU  - Ulas, Thomas
AU  - Beyer, Marc
AU  - Segal, Eran
AU  - Heneka, Michael
TI  - Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease.
JO  - ASN NEURO
VL  - 17
IS  - 1
SN  - 1759-0914
CY  - London
PB  - Sage Publishing
M1  - DZNE-2025-00627
SP  - 2506406
PY  - 2025
AB  - Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.
KW  - Animals
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Microglia: physiology
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Cell Proliferation: physiology
KW  - Mice, Transgenic
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Mice
KW  - Presenilin-1: genetics
KW  - Presenilin-1: metabolism
KW  - Disease Models, Animal
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - DEAD-box RNA Helicases: metabolism
KW  - DEAD-box RNA Helicases: genetics
KW  - Mice, Inbred C57BL
KW  - Humans
KW  - Male
KW  - Alzheimer’s disease (Other)
KW  - inflammasome (Other)
KW  - microglia (Other)
KW  - proliferation (Other)
KW  - transcriptome (Other)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - DEAD-box RNA Helicases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40387894
DO  - DOI:10.1080/17590914.2025.2506406
UR  - https://pub.dzne.de/record/278791
ER  -