Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony–stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

Engrafted glial progenitor cells yield long-term integration and sensory improvement in aged mice

Aging causes astrocyte morphological degeneration and functional deficiency, which impairs neuronal functions. Until now, whether age-induced neuronal deficiency could be alleviated by engraftment of glial progenitor cell (GPC) derived astrocytes remained unknown. In the current study, GPCs were generated from embryonic cortical neural stem cells in vitro and transplanted into the brains of aged mice. Their integration and intervention effects in the aged brain were examined 12 months after transplantation. Results indicated that these in-vitro-generated GPC-derived astrocytes possessed normal functional properties. After transplantation they could migrate, differentiate, achieve long-term integration, and maintain much younger morphology in the aged brain. Additionally, these GPC-derived astrocytes established endfeet expressing aquaporin-4 (AQP4) and ameliorate AQP4 polarization in the aged neocortex. More importantly, age-dependent sensory response degeneration was reversed by GPC transplantation. This work demonstrates that rejuvenation of the astrocyte niche is a promising treatment to prevent age-induced degradation of neuronal and behavioral functions.

The Cerebral Effect of Ammonia in Brain Aging: Blood–Brain Barrier Breakdown, Mitochondrial Dysfunction, and Neuroinflammation

Aging occurs along with multiple pathological problems in various organs. The aged brain, especially, shows a reduction in brain mass, neuronal cell death, energy dysregulation, and memory loss. Brain aging is influenced by altered metabolites both in the systemic blood circulation and the central nervous system (CNS). High levels of ammonia, a natural by-product produced in the body, have been reported as contributing to inflammatory responses, energy metabolism, and synaptic function, leading to memory function in CNS. Ammonia levels in the brain also increase as a consequence of the aging process, ultimately leading to neuropathological problems in the CNS. Although many researchers have demonstrated that the level of ammonia in the body alters with age and results in diverse pathological alterations, the definitive relationship between ammonia and the aged brain is not yet clear. Thus, we review the current body of evidence related to the roles of ammonia in the aged brain. On the basis of this, we hypothesize that the modulation of ammonia level in the CNS may be a critical clinical point to attenuate neuropathological alterations associated with aging.