The aged systemic milieu inhibits hippocampal neurogenesis and cognition through VCAM1

 DESCRIPTION (provided by applicant): Brain structure and function deteriorate with age, steadily driving cognitive impairments and susceptibility to degenerative disorders in adults. It has been recently demonstrated in the Wyss-Coray lab that brain function - specifically neurogenesis (the formation of new neurons) and cognitive function in the hippocampus, a key center for learning and memory- is inhibited in young mice exposed to an aged systemic environment. Additionally, the lab discovered that aged brain function can be enhanced through systemic circulation of young blood in aged animals. While the identity of systemic inhibitory and rejuvenating factors from aged and young plasma are beginning to be elucidated, the question of how and if these factors cross the blood brain barrier (BBB) and act directly on brain tissue to inhibit or promote neurogenesis and cognitive function remained unanswered. Additionally, whether the effects are mediated through peripheral interactions via the vasculature remains to be elucidated. Considering systemic circulating factors are in direct contact with brain endothelial cells (BECs) of the vasculature, it is possible that hippocampal deterioration or rejuvenation is mediated in part by changes in endothelial cell signaling. The proposed studies will test the hypothesis that an aged, inflammatory systemic environment induces endothelial cell activation and upregulation of adhesion molecules that are responsible, in part, for the communication between the systemic environment and the brain leading to functional and cognitive impairments with age. This proposal specifically focuses on vascular cell adhesion molecule 1 (VCAM1), whose soluble form was found to increase significantly in the blood plasma during human aging and following inhibition of brain function by aged systemic circulation in young animals. Aim 1 will determine the mechanisms underlying upregulation and shedding of VCAM1 by plasma factors, by treating isolated BECs with young and aged plasma and looking into signaling pathways that regulate VCAM1 transcriptionally and post-translationally, as well as direct transcriptional analysis of BECs from young mice exposed to the aged systemic environment through aged plasma injections or heterochronic parabiosis, in which the blood circulation of young and aged animals are conjoined. Aim 2 will determine whether VCAM1 is required for the detrimental effects of aged plasma on young hippocampal neurogenesis and cognition. VCAM1 function will be inhibited systemically via neutralizing monoclonal antibody, transgenic deletion specifically in BECs, or viral delivery-mediated Adam17 overexpression (enzyme responsible for cleavage and downregulation of VCAM1 function) following aged plasma injections into young mice, and hippocampal neurogenesis and cognitive functions carefully assessed. These studies will provide a better understanding of how the systemic environment negatively or positively regulates brain function. This project combines basic neuroscience, immunology, and molecular biology with translational research, paving the way for potential therapies that target the brain vasculature as a way to ameliorate cognitive decline and vascular degeneration associated with both healthy aging and multiple neurodegenerative diseases.

 DESCRIPTION (provided by applicant): Brain structure and function deteriorate with age, steadily driving cognitive impairments and susceptibility to degenerative disorders in adults. It has been recently demonstrated in the Wyss-Coray lab that brain function - specifically neurogenesis (the formation of new neurons) and cognitive function in the hippocampus, a key center for learning and memory- is inhibited in young mice exposed to an aged systemic environment. Additionally, the lab discovered that aged brain function can be enhanced through systemic circulation of young blood in aged animals. While the identity of systemic inhibitory and rejuvenating factors from aged and young plasma are beginning to be elucidated, the question of how and if these factors cross the blood brain barrier (BBB) and act directly on brain tissue to inhibit or promote neurogenesis and cognitive function remained unanswered. Additionally, whether the effects are mediated through peripheral interactions via the vasculature remains to be elucidated. Considering systemic circulating factors are in direct contact with brain endothelial cells (BECs) of the vasculature, it is possible that hippocampal deterioration or rejuvenation is mediated in part by changes in endothelial cell signaling. The proposed studies will test the hypothesis that an aged, inflammatory systemic environment induces endothelial cell activation and upregulation of adhesion molecules that are responsible, in part, for the communication between the systemic environment and the brain leading to functional and cognitive impairments with age. This proposal specifically focuses on vascular cell adhesion molecule 1 (VCAM1), whose soluble form was found to increase significantly in the blood plasma during human aging and following inhibition of brain function by aged systemic circulation in young animals. Aim 1 will determine the mechanisms underlying upregulation and shedding of VCAM1 by plasma factors, by treating isolated BECs with young and aged plasma and looking into signaling pathways that regulate VCAM1 transcriptionally and post-translationally, as well as direct transcriptional analysis of BECs from young mice exposed to the aged systemic environment through aged plasma injections or heterochronic parabiosis, in which the blood circulation of young and aged animals are conjoined. Aim 2 will determine whether VCAM1 is required for the detrimental effects of aged plasma on young hippocampal neurogenesis and cognition. VCAM1 function will be inhibited systemically via neutralizing monoclonal antibody, transgenic deletion specifically in BECs, or viral delivery-mediated Adam17 overexpression (enzyme responsible for cleavage and downregulation of VCAM1 function) following aged plasma injections into young mice, and hippocampal neurogenesis and cognitive functions carefully assessed. These studies will provide a better understanding of how the systemic environment negatively or positively regulates brain function. This project combines basic neuroscience, immunology, and molecular biology with translational research, paving the way for potential therapies that target the brain vasculature as a way to ameliorate cognitive decline and vascular degeneration associated with both healthy aging and multiple neurodegenerative diseases.