(A) novel chimeric phagocytic inducer and receptor for amyloid beta immunotherapy

Abstract

Dementia is a collective name for progressive brain syndromes affecting memory, thinking, behavior, and emotion. Of more than 100 forms of dementia, Alzheimer's disease (AD) accounts for 60-70% of all cases. The development of AD is known to be strongly associated with the progressive accumulation of beta-amyloid plaques and neurofibrillary tangles (NFTs) of hyper-phosphorylated tau proteins in the brain.The deposition of accumulated beta-amyloid and neurofibrillary tangles causes the loss of synapses and neuronal cell death, leading to the loss of short-term memory, impaired reasoning, and language dysfunction. However, until recently, there were no effective disease-modifying treatments for Alzheimer's disease. Despite the recent approval of Aducanumab, the first disease-modifying drug for AD treatment, several controversial issues about the FDA decision persist since Aducanumab did not prove the effects of improved cognitive recognition and the delay of disease progression in the clinicaltrials. Accordingly, there should be a further investigation for developing therapeutic drugs for Alzheimer’s disease.The first page of Chapter 1 introduced the pathology of Alzheimer’s disease (AD), immunotherapies for AD treatment, and the first approved monoclonal antibody, Aducanumab. In chapter 2, I described the research on a novel chimeric fusion protein, αAβ-Gas6, by engineering Gas6 protein, a bridging molecule for the clearance of dead cells via TAM (Tyro3, Axl, and MerTK) receptors. I observed that αAβ-Gas6 induced the Aβ burden reduction without excessive inflammatory responses and demonstrated improved functional outcomes with substantially reduced synapse elimination in AD mice models. In chapter 3, I showed the concept of chimeric phagocytic receptor (CPR) that exhibited the redirection to Aβ and enhanced phagocytic function.Based on these findings, our research of inflammatory modulator and CPR-P cell therapy for AD treatment by engineering protein or phagocytes suggests potential therapeutic strategies and the extension of the immunotherapy field.