Back to Search Start Over

The influence of APOEε4 on the pTau interactome in sporadic Alzheimer's disease.

Authors :
Thierry, Manon
Ponce, Jackeline
Martà-Ariza, Mitchell
Askenazi, Manor
Faustin, Arline
Leitner, Dominique
Pires, Geoffrey
Kanshin, Evgeny
Drummond, Eleanor
Ueberheide, Beatrix
Wisniewski, Thomas
Source :
Acta Neuropathologica; 5/21/2024, Vol. 147 Issue 1, p1-19, 19p
Publication Year :
2024

Abstract

APOE<superscript>ε4</superscript> is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE<superscript>ε4</superscript> is known to promote Aβ 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 APOE<superscript>ε3/ε3</superscript> and n = 5 APOE<superscript>ε4/ε4</superscript>), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE<superscript>ε3/ε3</superscript> and n = 10 APOE<superscript>ε4/ε4</superscript>). Our dataset includes 1130 and 1330 proteins enriched in IP<subscript>PHF1</subscript> samples from APOE<superscript>ε3/ε3</superscript> and APOE<superscript>ε4/ε4</superscript> groups (fold change ≥ 1.50, IP<subscript>PHF1</subscript>vs IP<subscript>IgG ctrl</subscript>). We identified 80 and 68 proteins as probable pTau interactors in APOE<superscript>ε3/ε3</superscript> and APOE<superscript>ε4/ε4</superscript> groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOE<superscript>ε3/ε3</superscript> vs APOE<superscript>ε4/ε4</superscript> 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 more likely to interact with pTau in APOE<superscript>ε4/ε4</superscript> vs APOE<superscript>ε3/ε3</superscript> cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE<superscript>ε4</superscript> carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE<superscript>ε4/ε4</superscript> cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOE<superscript>ε4</superscript> carriers, paving the way to the identification of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00016322
Volume :
147
Issue :
1
Database :
Complementary Index
Journal :
Acta Neuropathologica
Publication Type :
Academic Journal
Accession number :
177370694
Full Text :
https://doi.org/10.1007/s00401-024-02744-8