Shang Qi

Profile

Project Title: 

Amyloid-beta induced Membrane Permeability in Alzheimer's Disease

Summary: 

Alzheimer’s disease (AD) is the most common form of dementia and is a major public health burden. It is characterized by the accumulation of a small neuro-toxic peptide, amyloid-beta (Aβ) which forms fibrous plaques within the brain. The mechanism by which Aβ is toxic to neurons is not well understood, however its ability to disrupt membrane integrity and cellular homeostasis is believed to be central to Alzheimer’s disease pathology. Aβ can carpet the surface of the lipid bilayer and cause lipid extraction, and cause lipid oxidation. In addition, Aβ annular oligomers can form ion channels.

The self-association of Aβ, and subsequent interaction with the lipid bilayer is thought to cause disrupted cellular homeostasis which ultimately leads to hyper-phosphorylation of the micro-tubal associated protein tau, which results in cell death and dementia.  Aβ is reported to have various impacts on the lipid bilayer, but a clearer picture of Aβ influence on membranes is required. I will use a large tool-kit of biophysical, imaging and spectroscopic techniques to probe lipid membrane interactions.

Imaging the impact of Aβ (monomers; oligomers curvilinear protofibrils and fibrils) on membranes of various lipid compositions. Ca(II) influx and dye leakage from cells and synthetic vesicles will probe Aβ induce membrane permeability  Large unilamellar vesicles (LUVs) will be studied to investigate the influence of cholesterol, GM1, and charge on membrane-Aβ interactions. Nano-scale details of the bilayer will be imaged using Transmission Electron Microscopy (TEM) and cryo electron tomography(cryo-ET). Understanding how Aβ assemblies interact with cellular membranes is the first step to designing inhibitors to Aβ induced membrane disruption.

Supervisor:

• Dr John Viles

Research