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Comparing the Effects of Taurine and 3-Sulfopropanoic Acid, a Metabolite of Tramiprosate, on ApoE4 Pathological Aggregation: Implications for Alzheimer's Disease

ABSTRACT: Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease. Its pathological aggregation can be mitigated by tramiprosate and its metabolite 3-sulfopropanoic acid, along with their impact on the transcription of genes, expression of proteins, and production of lipids. Taurine (TRN) is a close chemical analogue of tramiprosate (TMP) with an extra carbon atom , demonstrating protective effects against aging. Using an integrated approach involving static light scattering, hydrogen-deuterium exchange mass spectrometry, molecular dynamics, and studies of cerebral organoids, we evaluated the effects of 3-sulfopropanoic acid and taurine on ApoE4 aggregation, as well as their impact on organoid transcriptomics and proteomics. Our results reveal that taurine effectively inhibits ApoE4 aggregation, comparable to 3-sulfopropanoic acid, and ameliorates the pathophysiological phenotype of ApoE4 in cerebral organoids, aligning it more closely with the ApoE3 phenotype. These findings suggest that taurine may have potential as a therapeutic agent against Alzheimer's disease, particularly in ApoE4/E4 carriers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292774 | GEO | 2025/05/14

REPOSITORIES: GEO

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Project description:Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factor for AD is the apolipoprotein E4 (E4) allele. APOE4 genotype has been shown to negatively impact on perivascular amyloid clearance, however, its direct influence along with the other APOE variants (APOE2 and APOE3) on the molecular integrity of the cerebrovasculature has not been largely explored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains on different APOE genotype backgrounds. We first interrogated changes between healthy control homozygote E2/E2, E3/E3 and E4/E4 cases to identify underlying genotype specific effects on cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. EIF2, nitric oxide and sirtuin signaling pathways were the top significantly altered pathways in E4/E4 compared to E2/E2 cases. We used a Two-way ANOVA analysis to identify AD-dependent changes and their interactions with APOE genotype. The highest number of significantly regulated proteins from this interaction was observed in E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E4/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E3/E4 cases. These proteomic changes provide novel insights to explain the longstanding link between APOE4 and cerebrovascular dysfunction. The early and converging APOE4 dependent changes we identified could provide novel targets in the cerebrovasculature for developing disease modifying strategies to mitigate the effects of APOE4 genotype on increasing the risk for, and the path towards AD pathogenesis.

Dataset Information

Comparing the Effects of Taurine and 3-Sulfopropanoic Acid, a Metabolite of Tramiprosate, on ApoE4 Pathological Aggregation: Implications for Alzheimer's Disease

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