Anti-RPS23RG1 Nanoantibody as Novel Therapeutic and Research Reagents for Alzheimer’s Disease.

Abstract Alzheimerandapos s disease AD is the most common dementia in the elderly Currently there is no cure for the disease Pathologically AD is characterized by the presence of extracellular amyloid A plaques and intracellular tau neurofibrillary tangles in patientandapos s brain Although being vigorously pursued multiple attempts targeting on A generation clearance have been failed in Clinical trials mainly due to toxic side effects and lack of efficacy As reported recently in Scientific Reports we identified the human RPS RG gene with the ability to reduce A production and tau phosphorylation We also showed that RPS RG overexpression counteracted A oligomer oA induced synaptic loss and cognitive impairments by activating adenylate cyclase PKA signaling pathways which in turn caused the activation of CREB an important transcription factor regulating learning and memory and the inactivation of GSK an important kinase inducing tau hyperphosphorylation Thus RPS RG can be further exploited for its therapeutic potential in AD The purpose of this project is to generate an agonistic activating nanoantibody targeting RPS RG to promote RPS RG mediated synaptic and cognitive protection against AD Nanantibody nAb is a distinctive type of antibody fragment derived from camelid heavy chain only antibody HCAb As a therapeutic candidate nAb holds many superior properties over conventional antibodies In addition agonistic activating antibodies have been widely reported and used in many areas of research and therapy including those targeting G protein coupled receptors GPCRs In this proposal we will generate humanized nanoantibodies that will bind RPS RG and activate downstream signaling pathways We will examine the expression of RPS RG in AD postmortem brains and its correlation with the severity of premortem cognitive decline in human patients with severe memory loss mild memory impairment MCI or normal cognition as control We will also examine its ability to activate downstream signaling pathways to counteract synaptic and cognitive decline in both in vitro and in vivo animal models of AD We expect that RPS RG is downregulated in AD patient brains and its reduction correlates with the severity of dementia in AD and MCI patients and that agonistic RPS RG nanoantibodies reduce A and phosphorylated tau levels and mitigate synaptic loss and cognitive impairment in an PKA dependent manner in AD mice Our results should lay a foundation for the future development of RPS RG nanoantibodies as therapeutics in AD Narrative Synaptic deficits mediated by oligomeric A and hyperphosphorylated tau underlies cognitive decline in Alzheimerandapos s disease AD In this project we propose to develop biologics nanoantibodies targeting novel therapeutic target RSP RG to counteract AD associated synaptic and cognitive impairments The outcome of this study may lay a foundation for future development of therapeutic reagents in AD