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Peripherally-expressed apoE4 impairs brain functions and exacerbates amyloid pathogenesis by compromising cerebrovascular functions

ABSTRACT: The apolipoprotein E4 (APOE4) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE is a lipid carrier abundantly expressed in both brain and periphery. As peripheral apoE is separated from brain apoE by the blood-brain barrier, it remains unclear whether peripheral apoE impacts brain functions and AD pathogenesis. To investigate this, we developed novel mouse models that conditionally express human APOE3 or APOE4 only in the liver with no detectable apoE in the brain. We found that liver-expressed apoE4 compromised synaptic plasticity and cognitive behaviors likely by impairing cerebrovascular functions. Remarkably, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate a pathogenic effect of peripheral apoE4, providing strong rationale for targeting peripheral apoE to treat AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE125501 | GEO | 2022/06/15

REPOSITORIES: GEO

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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.

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Peripherally-expressed apoE4 impairs brain functions and exacerbates amyloid pathogenesis by compromising cerebrovascular functions

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