Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain

Abstract

Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL‐6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.

Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging

“…Cell adhesion emerged as a hallmark of NSC aging in our study. The migratory properties of neuroblasts has started to be examined with age [44][45][46][47] and in the context of innervating distal tumors 73 . But the changes in migration and adhesion in quiescent and activated NSCs, the upstream NSC populations that give rise to migratory neuroblasts, remain largely unknown.…”

“…Interestingly, many of these age-related chromatin changes occur in regulatory regions of cell adhesion and migration genes. The migratory properties of NSCs and neuroblasts has started to be examined with age [55][56][57][58][59] and in the context of innervating distal tumors 88 . Recent live-cell imaging of SVZ wholemounts showed that aNSC and NPC migration distance and speed decreased with age 59 .…”

“…Quiescent NSCs line the ventricles and can become activated (aNSCs) to give rise to neural progenitors (NPCs) and neuroblasts that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB) 10, 42,43 . While neuroblast migration has begun to be examined in older animals [44][45][46][47] , the adhesive and migratory properties of quiescent and activated NSCs and their progenitors in vivo during aging remain largely unstudied. As adhesion to the niche plays a key role in regulating NSC stemness and function 48 , we assessed quiescent and activated NSC localization in vivo by immunostaining of coronal brain sections from young and old individuals (Fig.…”

“…Neuroblasts then migrate long distances along the rostral migratory stream (RMS) to the olfactory bulb (OB) to give rise to new neurons (neurogenesis) 3,14,54 . While NSC/NPC and neuroblast migration has begun to be examined in older animals [55][56][57][58][59] , the adhesive and migratory properties of quiescent and activated NSCs (and their progenitors) has not been systematically studied in vivo during aging.…”

Research advances on antioxidation, neuroprotection, and molecular mechanisms of Lycium barbarum polysaccharides

“…During normal aging, due to the decline in the metabolic function of neurons and astrocytes, accumulation of abnormal proteins and DNA breakage, lipids and other macromolecular substances are gradually oxidized and cannot be degraded by the lysosomes. In addition, the destruction of proteins during aging increases and affects the phagocytosis of cells, which leads to the accumulation of denatured proteins in lysosomes [35, 36]. Several studies have shown that LBPs can promote the neural differentiation of neural stem cells and inhibit the abnormal differentiation of glial cells, thereby improving brain function during aging and in neurodegenerative diseases, such as AD and macular degeneration.…”