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.

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

“…Administration of bacoside A, one of the main components of BM, significantly inhibits TNF-α and many inflammatory enzymes, Metalloproteinase 3 (MMP-3) and caspases 1 and 3, and the release of IL-6 from microglial cells, which is the main modulator of neuroinflammation in the Central Nervous System (CNS) [47,124]. These activated microglia produce pro-inflammatory proteins, which lead to prolonged neuroinflammation and cause critical processes associated with neurodegenerative diseases [125,126]. In addition to Bacosides, indolic compounds and phenolic acids are also responsible for the anti-inflammatory action, reducing cyclooxygenase 2 (COX-2) and Prostaglandin C (cPGES) expression [41,95,127,128].…”

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

“…As a dividing cell population, microglia are susceptible to cellular senescence, and senescent microglia can perpetuate CNS inflammation and injury 11 . Importantly, aged microglia demonstrate decreased turnover and limited myelin debris phagocytosis suggesting impaired homeostatic functions 12,13 . Like an ouroboros, CNS injury and inflammation can likewise accelerate microglial senescence.…”