Clearance of amyloid-beta in Alzheimer's disease: To understand the pathogenesis and develop potential therapies in animal models

Author: Yan-Jiang Wang

Wang, Yan-Jiang, 2010 Clearance of amyloid-beta in Alzheimer's disease: To understand the pathogenesis and develop potential therapies in animal models, Flinders University, School of Medicine

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Alzheimer's disease (AD) is the most common cause of dementia. No strong disease-modifying treatments are currently available. Amyloid-beta peptide (Abeta) appears to play a pivotal role in the pathogenesis of AD. We focused our interest on revealing the pathogenesis of the disease and developing novel therapeutic modalities. The thesis consists of three projects: 1. Prevention of AD by intramuscular delivery of an anti-Abeta single chain antibody (scFv) gene: Immunotherapy is effective in removing brain Abeta - but was associated with detrimental effects. In the present study, the gene of an anti-Abeta scFv was delivered in the hind leg muscles of APPSwe/PS1dE9 mice with adeno-associated virus at three months of age. Six months later, we found that brain Abeta accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated mice relative to enhanced green fluorescence protein (EGFP)-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of AD, and would be a promising non-inflammatory immunological modality for prevention and treatment of AD. 2. Prevention of AD with grape seed derived polyphenols: Polyphenols extracted from grape seeds are able to inhibit Abeta-aggregation, reduce Abeta production and protect against Abeta neurotoxicity in vitro. We investigated the therapeutic effects of a polyphenol-rich grape seed extract (GSE) in vivo. APPSwe/PS1dE9 transgenic mice were fed with normal AIN-93G diet (control diet), AIN-93G diet with 0.07% curcumin, or diet with 2% GSE beginning at 3 months of age for 9 months. Total phenolic content of GSE was 592.5 mg/g dry weight, including gallic acid, catechin, epicatechin and proanthocyanidins. Long-term feeding of GSE diet was well tolerated. The Abeta-levels in the brain and serum of the mice fed with GSE were reduced by 33% and 44% respectively compared with the mice fed with the control diet. Amyloid plaques and microgliosis in the brain of mice fed with GSE were also reduced by 49% and 70% respectively. In conclusion, polyphenol-rich GSE is promising to be a safe and effective drug to prevent the development of AD. 3. Roles of p75NTR in the development of AD: P75NTR has been suggested to mediate Abeta induced neurotoxicity. However, its role in the development of AD is undetermined. APPSwe/PS1dE9 transgenic mice were crossed with p75NTR knockout mice to generate APPSwe/PS1dE9 mice with p75NTR gene deleted. P75NTR mainly expressed in the basal forebrain neurons and degenerative neurites in neocortex and hippocampus. Genetic deletion of p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Abeta levels, but increased the insoluble Abeta accumulation and Abeta plaque formation in the brain. P75NTR deletion decreased Abeta production of cortical neurons in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Abeta42 peptide in vitro, and reduced local Abeta plaques after hippocampus injection in vivo. Our data suggest that p75NTR plays an important role in AD development and may be a valid therapeutic target for the treatment of AD.

Keywords: Alzheimer's disease,amyloid-beta,immunotherapy,single chain antibody,grape seed extract,polyphenol,p75NTR
Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2010
School: School of Medicine
Supervisor: Prof. Xin-Fu Zhou