Dataset Information

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

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Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate.

Nemergut Michal M Marques Sérgio M SM Uhrik Lukas L Vanova Tereza T Nezvedova Marketa M Gadara Darshak Chandulal DC Jha Durga D Tulis Jan J Novakova Veronika V Planas-Iglesias Joan J Kunka Antonin A Legrand Anthony A Hribkova Hana H Pospisilova Veronika V Sedmik Jiri J Raska Jan J Prokop Zbynek Z Damborsky Jiri J Bohaciakova Dasa D Spacil Zdenek Z Hernychova Lenka L Bednar David D Marek Martin M

Molecular neurodegeneration 20230606 1

<h4>Background</h4>Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.<h4>Methods</h4>Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium m ...[more]

PMID: 37280636

Similar Datasets

Project description:APOE4 is the major genetic risk factor for sporadic Alzheimers disease (AD). Although APOE4 is well known to promote Abeta pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n=5 APOE3 and n=5 APOE4), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti-pTau PHF1 and anti-Abeta 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n=11 APOE3 and n=10 APOE4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOE3 and APOE4 groups (FC over 1.50, IPPHF1 versus IPIgG ctrl). We identified 80 and 68 proteins as strong pTau interactors in APOE3 and APOE4 groups, respectively (SAINT score above 0.80; FDR under 5%). A total of 47/80 proteins were identified as strong pTau interactors only for APOE3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as strong pTau interactors only for APOE4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE4 cases. Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression to Abeta-affected brain regions of APOE4 carriers, paving the way to the identification of potential new therapeutic targets. This entry contains the mass spectrometric raw files for the immune purifications.

			Action	DRS
	APOE3_10min_2.raw	Raw
	APOE3_10min_3.raw	Raw
	APOE3_1min_2.raw	Raw
	APOE3_1min_3.raw	Raw
	APOE3_2min_2.raw	Raw