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

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.

SUBMITTER: Berglund R

PROVIDER: S-EPMC10776874 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Berglund Rasmus R Cheng Yufei Y Piket Eliane E Adzemovic Milena Z MZ Zeitelhofer Manuel M Olsson Tomas T Guerreiro-Cacais Andre Ortlieb AO Jagodic Maja M

Nature communications 20240109 1

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 ...[more]

PMID: 38195627

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Project description:Neuroinflammation has long been considered a driver of Alzheimer's disease progression. However, experiments developed to explore the interaction between neuroinflammation and Alzheimer's disease (AD) pathology showed a surprising reduction in amyloid beta (A?) plaque deposition. We sought to understand this unexpected outcome by examining microglia phenotypes during chronic neuroinflammation.Using an adeno-associated virus vector carrying hIL-1? cDNA, inflammation was induced in one hippocampus of 8-month-old amyloid precursor protein (APP)/PS1 mice for 4 weeks, while the other hemisphere received control injections. Bone marrow chimeras and staining analysis were used to identify the origins and types of immune cells present during sustained inflammation. Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS) immunoreactivity were used as markers of alternatively activated and classically activated cells, respectively, and changes in cellular uptake of A? by Arg1+ or iNOS+ microglia was demonstrated by confocal microscopy. To determine if an anti-inflammatory phenotype was present during neuroinflammation, RNA was extracted on flow-sorted microglia and rt-PCR was performed. Interleukin-4 injection was used to induce alternatively activated cells, whereas a minipump and intrahippocampal cannula was used to deliver an interleukin (IL)-4R? antibody to block the induction of Arg1+ cells in the setting of sustained IL-1? expression.We observed a robust upregulation of centrally derived Arg1+ microglia present only in the inflamed hemisphere. Furthermore, in the inflamed hemisphere, greater numbers of Arg1+ microglia contained A? when compared to iNOS+ microglia. RNA isolated from flow-sorted microglia from the inflamed hemisphere demonstrated elevation of mRNA species consistent with alternative activation as well as neuroprotective genes such as BDNF and IGF1. To explore if Arg1+ microglia mediated plaque reduction, we induced Arg1+ microglia with IL-4 and observed significant plaque clearance. Moreover, when we reduced Arg1+ microglia induction in the context of neuroinflammation using an anti-IL-4R? antibody delivered via intrahippocampal cannula, we observed a clear correlation between numbers of Arg1+ microglia and plaque reduction.Together, these findings suggest that Arg1+ microglia are involved in A? plaque reduction during sustained, IL-1?-dependent neuroinflammation, opening up possible new avenues for immunomodulatory therapy of AD.

Dataset Information

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

Publications

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

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