Work

P3‐045: Beneficial Effects of Plasma Fractions on Neurogenesis for Age Related Cognitive Disorders

Year: 2019

Type: article

Abstract: Age-dependent decline in neurogenesis is a multifactorial process resulting from an increased neuroinflammatory state, decreased proliferation of neuronal stem cells, decreased cell survival and reduction in new-born neuron maturation. There are no interventions that aim to enhance neurogenesis despite a therapeutic potential and great clinical need. Heterochronic parabiosis between young and old parabionts has demonstrated that neurogenesis can be increased in aged organisms facilitated by factors present in young plasma, providing initial proof of concept for an approach to rejuvenate neurogenic processes in the CNS and enhance cognition. To advance this concept therapeutically, we have characterized human plasma, and fractions thereof, for the ability to enhance neurogenesis in aging mice. We confirmed that human plasma from young, 18–22 year old, donors reverses age-related cognitive decline and enhances hippocampal neurogenesis and cell survival in aged immunocompromised NSG mice, while plasma from aged individuals (62-68 years old) has detrimental effects in young NSG mice. Utilizing cell-based assays we identified a plasma fraction which enhanced neuronal outgrowth and synaptic connectivity. We then utilized this plasma fraction to reverse the age-related decline in neurogenesis and cognitive dysfunction. Plasma fraction treatment enhanced neuroregenerative properties in both middle aged and aged mice above the effect observed with whole plasma and provided long-lasting effects on neurogenesis without exhaustion of the neuronal progenitor cells. Multiple endpoints associated with age-related decline, such as neuroinflammation, cell fate changes, decreased synaptic connections and cognition deficits were also affected. We demonstrate a long-lasting effect of a therapeutically relevant plasma fraction on cell survival and neurogenesis by preferentially driving cells towards a neuronal fate. Together, these data provide the rationale for clinical development of this plasma fraction for the treatment of cognitive decline in diseases of aging.

Source: Alzheimer s & Dementia

DOI: 10.1016/j.jalz.2019.06.3071