Apolipoprotein E4 (ApoE4) as a novel Alzheimer’s disease (AD) intervention target

Neurodegenerative diseases in particular Alzheimer’s disease (AD) are becoming highly prevalent in society based on an increase in life expectancy over the years. In fact, there is predicted to be well over 100 million AD cases in 30 years time. Alzheimer’s disease has two major features or hallmarks, amyloid beta plaques and intracellular tangles of tau which contribute to degradation in the cerebral cortex and subcortical regions of the brain. These factors decrease and prevent function of major components of cells including interfering with cell signal transduction, membrane transport and mitochondrial function.

ApoE4 is very significant in Alzheimer’s disease with its effects including the increase of amyloid beta aggregation and a decrease in its clearance as well as increase in tau phosphorylation and tangle formation which are the two hallmarks of AD. ApoE4 when present is one of the highest genetic risk factors of Alzheimer’s disease progression increasing chances of developing AD by three times. ApoE is regularly involved in the metabolism of fats in the body and plays a small role in inflammation and immune response. When lipidated specific roles include Amyloid clearance, synaptogenesis, neuroimmune modulation and cerebrovascular function. However, lipidation of ApoE4 is far less effective than the other variants ApoE2 and ApoE3 and causes toxic effects. Therefore, the focus for this research examines potential inhibitors for ApoE4 to potentially reduce the toxic effects of non-lipidated ApoE4. Using a phage displayed random peptide library and biopanning techniques potential ApoE4 inhibitors that show high binding affinity to the target is aimed to be identified and examined.