Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement

Abstract

Aging drives cognitive decline, and mitochondrial dysfunction is a hallmark of age-induced neurodegeneration. Recently, we demonstrated that astrocytes secrete functional mitochondria (Mt), which help adjacent cells to resist damage and promote repair after neurological injuries. However, the relationship between age-dependent changes in astrocytic Mt function and cognitive decline remains poorly understood. Here, we established that aged astrocytes secret less functional Mt compared to young astrocytes. We found the aging factor C-C motif chemokine 11 (CCL11) is elevated in the hippocampus of aged mice, and that its level is reduced upon systemic administration of young Mt, in vivo. Aged mice receiving young Mt, but not aged Mt improved cognitive function and hippocampal integrity. Using a CCL11-induced aging-like model in vitro, we found that astrocytic Mt protect hippocampal neurons and enhance a regenerative environment through upregulating synaptogenesis-related gene expression and anti-oxidants that were suppressed by CCL11. Moreover, the inhibition of CCL11-specific receptor C-C chemokine receptor 3 (CCR3) boosted the expression of synaptogenesis-related genes in the cultured hippocampal neurons and restored the neurite outgrowth. This study suggests that young astrocytic Mt can preserve cognitive function in the CCL11-mediated aging brain by promoting neuronal survival and neuroplasticity in the hippocampus.

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

“…More recently, others have observed that, alongside functional mitochondria, astrocytes also secrete the mitochondrial-genome-encoded small bioactive peptide humanin that is transported to microglia, reducing proinflammatory outcomes [ 312 ]. Notably, the efficacy of mitochondria transfer is intrinsically related to the age of the donor tissue/cell, as young mitochondria show better performance than older ones [ 313 ]. Corroborating these findings, mitotherapy with healthy young mitochondria obtained from the livers of young mice showed positive results in restoring the hippocampal mitochondrial bioenergetics of aged mice [ 314 ].…”