Bimodal effects of young and aged human plasma on neurogenesis and cognition: Developing plasma derived therapeutics for cognitive disorders of aging E. Czirr, I.D. Gallager, S.S. Minami, S.P. Braithwaite Alkahest Inc., San Carlos, CA, USA
Advanced age is the biggest risk factor for many cognitive disorders including Alzheimer's Disease, and even healthy aging is associated with a decline in cognitive function. Previous work has shown that exposing an aged mouse brain to a young systemic environment, either by parabiosis or by mouse plasma transfer results in enhanced cognitive function and improved histological correlates, while exposure of the young mouse brain to an aged systemic environment has the opposite effects. This data suggests the presence of detrimental factors in aged plasma and beneficial factors in young plasma. To extend the mouse-on-mouse data to human plasma we treated young immunodeficient NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) with human plasma from 65-68-year old donors, and old NSG mice with plasma from 18-22-year old donors. We found that systemic injections of old human plasma into young NSG mice results in decreased neurogenesis and conversely, treatment with young human plasma improves neurogenesis and cognition in aged animals. Subsequently, we were able to identify a plasma fraction that enhances both neurogenesis and cognition in aged animals beyond the enhancement seen with young plasma, suggesting that the plasma fraction contains an improved composition of beneficial factors. In contrast to whole human plasma, the plasma fraction allows testing in wild-type (C57BL/6) mice with an intact immune system, where it also shows activity. The generation of improved and better defined plasma products opens the path towards clinical application in aging associated disorders.