Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer’s Disease Drug Candidate

ABSTRACT: The development of treatment for Alzheimer’s Disease (AD) is hindered by a limited understanding of its structural basis. Apolipoprotein E (APOE) ε4 genotype is the most important risk factor for late-onset AD. APOE4 differs from the APOE3 isoform by a single mutation, C112R. Here, we employ crystallography, biophysical methods and computer simulations to dissect the “domino-like” effect of C112R substitution on APOE4 behaviour. We found that the mutation induces long-distance (>15 Å) conformational changes leading to geometrically distinct T-shaped dimeric unit of APOE4 compared to APOE3. By mutagenesis, we demonstrate that the APOE4 unit is more prone to aggregation than that of the APOE3. AD drug candidate tramiprosate and metabolite 3-sulfopropanoic acid induce APOE3-like conformational behaviour in APOE4 and suppress its aggregation propensity. Omics analysis of APOE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage product of excess cholesterol. Our results connect the APOE4 structure with its aggregation propensity, which can be further exploited in drug development for neurodegeneration and ageing.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell

DISEASE(S): Acute Leukemia,Brain Cancer

SUBMITTER: Lenka Hernychova  

LAB HEAD: Prof. Jiri Damborsky

PROVIDER: PXD036416 | Pride | 2023-07-20

REPOSITORIES: Pride