Apolipoprotein E in neurobiology of aging and cardiovascular disease

My research focuses on the structural and functional analysis of lipoproteins, specifically apolipoprotein E (apoE). ApoE is  an anti-atherogenic protein, which is a key mediator of cholesterol homeostasis in the plasma and the brain. In the plasma, apoE plays a critical role as an anti-atherogenic apolipoprotein in cardiovascular and cerebrovascular diseases and regulates the transport of lipids and the dynamics of inter conversion of lipoproteins. My lab utilizes spectroscopic, biophysical and cell biology approaches to investigate the structure/function relationship in apoE in terms of its cholesterol and triglycerides transport role . One of the projects involves examining the effect of acrolein on the structure and function of apoE and the consequences in lipoprotein metabolism. Acrolein is a pro-oxidant that is generated as a metabolite of age-related oxidative stress and is present in high concentrations in the gaseous phase of tobacco smoke. The goal of this project is to determine if exposure to second hand smoke predisposes individuals towards developing a pro-atherogenic profile, an established risk factor for heart disease and stroke. Involuntary exposure to second hand smoke is particularly relevant in the case of the pediatric population and the elderly.

In the brain, apoE plays a role in cholesterol delivery to the neurons. However, it is also associated with Alzheimer’s disease (AD), an age-related neurodegenerative disorder, in which the polymorphic feature of apoE is directly relevant. ApoE exists as three different isoforms (apoE2, apoE3 and apoE4) with the allelic frequency of apoe2, apoe3 and apoe4 being 0.07, 0.78 and 0.15, respectively. ApoE4- bearing individuals are at a high risk for developing AD. Analogous to its role in the plasma, apoE functions as a mediator for cholesterol delivery to the neurons. Our laboratory examines the structural and functional basis of the role of apoE4 in the amyloid pathogenesis, a characteristic feature in AD involving misfolded amyloid beta peptide (Aβ).

Lastly, we investigate the structural basis of α-synuclein, a protein that is misfolded is Parkinson’s disease (PD). Alpha-synuclein is predominantly unstructured in the lipid-free state, but adopts a helical structure similar to apolipoproteins in the membrane -bound state when present in the presynaptic vesicle environment. It irreversibly transitions to a β-sheet structure and is deposited as aggregates in the Lewy bodies, a hall mark pathological feature of PD.