Graduation Year

2016

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Jianfeng Cai, Ph.D.

Co-Major Professor

Chuanhai Cao, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Li-June Ming, Ph.D.

Keywords

AApeptide, Alzheimer's diseases, peptitomimetics, small molecules

Abstract

Alzheimer's diseases (AD) has been discovered and under research for more than 70 years,[1] However there is no cure for these progressive and devastating diseases. There are four major pathologies for Alzheimer's diseases: Tau phosphrylation[2], ApoE pathology[3], AchE activity pathology[1], and pathology of AD Figure 1.1 shows the pathway of Aβ pathogenesis. In the light of newly discovered peptidomimetics, AApeptides. We moved on to the new era of research to discover their potential of transmembrane activity and anti-Alzheimer's acitiviy. Our study has shown that: 1) Our synthesized γ-AApeptide and α-AApeptide has comparable ability of transduction passing through the cell membrane; 2) AApeptide has potential as drug carrier for intracellular delivery, due to their character of both improved cellular translocation efficiency and enhanced stability against proteolytic hydrolysis compared to AApeptides; 3) AApeptide which were identified by combinatory chemistry and antibody binding assay, has very good potential for the diagnosis and treatment of Alzheimer's diseases.

On the other hand, Melatonin has been long been used as a small molecule pharmacy to regulate circadian syndrome. Recently, its great potential of anti-Alzheimer’s disease has been discovered and its mechanism has been studied,[4] such as tau pathology and anti-oxidative stress. However, its extracellular function, especially the interaction with pathological protein β-amyloid and melatonin receptor regulation in neuroblastoma cells, was rarely reported. Our data indicated that melatonin can prevent Aβ aggregation and then further prevent Aβ aggregation related cascade response. Melatonin also helps cell clear out Aβ in mitochondria, and recover the function of mitochondria. The function of melatonin anti-aging or AD has been reported by several groups and they are 1). This effect appears to be due to direct hydrophobic, residue-specific interactions between melatonin and Aβ, whereby melatonin disrupts imidazole-carboxylate salt bridges critical for Aβ fibrillar formation[5]; 2). melatonin has been shown to protect against Aβ-induced neurotoxicity in vitro and in vivo, most probably through its ability to affect antioxidant enzymes and to be a potent free radical scavenger/antioxidant against toxic oxygen- and nitrogen-based reactants[5]; However, its extracellular function, especially the interaction with pathological protein β-amyloid and regulation of melatonin receptor (MT1) was seldom reported. Herein, based on in vitro assays established, we would further discover the potential of melatonin derivatives in treating Alzheimer's Diseases.

Our Hypothesis are: Aß metabolite problem/over production result in the accumulation, and lead to aggregation is the cause of Alzheimer’s disease. AApeptide and Melatonin derivatives can bind to Aß and block the aggregation of β amyloid monomers, decrease the toxicity of Aß to neurons and slow the progressive of Alzheimer’s diseases. In addition, AApeptide which mimic transmembrane peptide Tat will have similar transmembrane function.

Share

COinS