MALLEABILITY OF AGING PROCESSES VIA PLASMA BASED THERAPEUTICS

Abstract

Age is the major risk factor for Alzheimer's disease and the majority of neurodegenerative disorders. Being able to modulate fundamental aging processes may therefore have broad therapeutic utility and act upstream of other risk factors for disease. Whether biological aging processes can be reversed, and whether multiple age-related mechanisms can be impacted for therapeutic benefit, is a challenging proposition through traditional therapeutic routes. Building on understandings from parabiosis and plasma infusions, therapeutically viable plasma fractions were tested for their ability to modulate CNS-relevant endpoints in in vitro cell culture and in vivo systems. Testing synaptic/network activity and morphology measurements in primary neuronal cultures and cognitive behavior and a broad array of histological analyses in aged mice was performed to assess broad mechanisms of action. A prioritized plasma fraction was demonstrated to enhance network activity in neuronal cultures and to enhance cognitive performance in a range of behavioral paradigms. The plasma fraction resulted in enhancement of activity as indicated by elevated cfos expression, reduced neuroinflammation and enhanced neurogenesis. Effects were maintained for a period of months after dosing was completed, indicative of long term efficacy in the brain. Beneficial activities have been demonstrated in three independent lines of mice - C57Bl6, NSG and α-synuclein transgenics - demonstrating broad fundamental activity. A plasma fraction has been identified that has the ability to modulate multiple underlying mechanisms of relevance in age-related disorders including Alzheimer's disease. These fractions are being advanced into clinical testing to understand potential as transformative therapeutics for patients.