Therapeutic approach targeting apolipoprotein E binding region and low-density lipoprotein receptor for Alzheimer��s disease

Abstract

Approximately 13% of the population over the age of 65 years is estimated to have AD. The total number of cases is expected to increase over the coming decades. The apolipoprotein E (ApoE) genotype is the greatest genetic determinant for Alzheimer’s disease (AD) development. The ApoE4 allele increases the risk of AD by 4 to 14 fold while the ApoE2 allele has an opposing effect; decreasing risk. Indeed many studies have demonstrated that carriers of the ApoE2 allele are associated with greater likelihood of survival to advanced age, superior verbal learning ability in advanced age, and reduced accumulation of amyloid pathology in the aged brain. In addition, it is known that ApoE proteins have different affinities for the low-density lipoprotein receptor (LDLR), with ApoE2 having the weakest binding to the LDL receptor at < 2% relative to ApoE3 and E4. Because ApoE2 has shown protective effects in regard to AD, a novel approach for ApoE4 carriers may be to create a peptide antagonist that blocks the ApoE interactions with LDLR at its 135-150 N-terminal binding domain. This peptide may create a more ApoE2-like structure by decreasing the affinity of ApoE4 for LDLR thereby reducing AD onset, memory impairment, and amyloid plaque formation. In this review, we will discuss the different detrimental effects that ApoE4 can cause. Most importantly, we will review how ApoE4 binding to LDLR promotes AD pathogenesis and how blocking ApoE4 binding may be a promising novel therapeutic approach for AD.