The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34

Rasmus Berglund (), Yufei Cheng, Eliane Piket, Milena Z. Adzemovic, Manuel Zeitelhofer, Tomas Olsson, Andre Ortlieb Guerreiro-Cacais and Maja Jagodic
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Rasmus Berglund: Karolinska University Hospital
Yufei Cheng: Karolinska University Hospital
Eliane Piket: Karolinska University Hospital
Milena Z. Adzemovic: Karolinska University Hospital
Manuel Zeitelhofer: Karolinska Institutet
Tomas Olsson: Karolinska University Hospital
Andre Ortlieb Guerreiro-Cacais: Karolinska University Hospital
Maja Jagodic: Karolinska University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Microglia harness an unutilized health-promoting potential in age-related neurodegenerative and neuroinflammatory diseases, conditions like progressive multiple sclerosis (MS). Our research unveils an microglia population emerging in the cortical brain regions of aging mice, marked by ERK1/2, Akt, and AMPK phosphorylation patterns and a transcriptome indicative of activated autophagy - a process critical for cellular adaptability. By deleting the core autophagy gene Ulk1 in microglia, we reduce this population in the central nervous system of aged mice. Notably, this population is found dependent on IL-34, rather than CSF1, although both are ligands for CSF1R. When aging mice are exposed to autoimmune neuroinflammation, the loss of autophagy-dependent microglia leads to neural and glial cell death and increased mortality. Conversely, microglial expansion mediated by IL-34 exhibits a protective effect. These findings shed light on an autophagy-dependent neuroprotective microglia population as a potential target for treating age-related neuroinflammatory conditions, including progressive MS.

Date: 2024
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DOI: 10.1038/s41467-023-44556-6

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