Abstract
Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.
Highlights
Adult neurogenesis, the process by which new functional neurons are generated and integrated into existing neuronal circuits of the adult brain, occurs in two specific regions of the mouse central nervous system (CNS): the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ)[1]
We provide evidence that Growth Differentiation Factor 11 (GDF11) does not cross the blood brain barrier (BBB) and that the endothelial cells of the cerebral vasculature are responsive to GDF11, suggesting that GDF11 exerts at least a portion of its CNS effects through the vasculature
As aging causes a decline in hippocampal neurogenesis[5], we investigated whether this treatment could increase the number of newborn neurons, neural stem cells or neural progenitors/immature neurons in the hippocampus of old mice[18]
Summary
The process by which new functional neurons are generated and integrated into existing neuronal circuits of the adult brain, occurs in two specific regions of the mouse central nervous system (CNS): the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ)[1]. Heterochronic parabiosis, through which systemic factors circulating in young and old mouse blood are shared, positively influences neurogenesis, cerebral vasculature, neuronal activity, synaptic plasticity and cognitive function in old mice[9,10,11]. We provide evidence that GDF11 does not cross the blood brain barrier (BBB) and that the endothelial cells of the cerebral vasculature are responsive to GDF11, suggesting that GDF11 exerts at least a portion of its CNS effects through the vasculature This distinguishes GDF11 from other individual circulating factors that have been shown to modulate aging in the brain by entering the CNS and acting directly on neural cells[4]. GDF11 may be a novel rejuvenating factor that acts on vasculature within and outside of neurogenic brain regions
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