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载脂蛋白 Eε4 增强了淀粉样 β 对纵向 tau 病理的影响。

APOEε4 potentiates amyloid β effects on longitudinal tau pathology.

机构信息

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

出版信息

Nat Aging. 2023 Oct;3(10):1210-1218. doi: 10.1038/s43587-023-00490-2. Epub 2023 Sep 25.

DOI:10.1038/s43587-023-00490-2
PMID:37749258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10592050/
Abstract

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([F]AZD4694) and tau ([F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aβ effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the living human brain.

摘要

载脂蛋白 E ε4 (APOEε4) 等位基因影响阿尔茨海默病 (AD) 病理生理进展的机制尚不清楚。在这里，我们测试了 APOEε4 携带状态和淀粉样蛋白-β (Aβ) 负担与纵向 tau 病理的关联。我们对跨越衰老和 AD 谱的 94 名个体进行了纵向评估，这些个体在基线时接受了临床评估、APOE 基因分型、磁共振成像、正电子发射断层扫描 (PET) 用于 Aβ ([F]AZD4694) 和 tau ([F]MK-6240)，以及 2 年的 tau-PET 随访扫描。我们发现，APOEε4 携带状态增强了 Aβ 对 2 年内纵向 tau 积累的影响。APOEε4 增强的 Aβ 对 tau-PET 负担的影响是通过纵向血浆磷酸化 tau 第 217 位苏氨酸 (p-tau217) 的增加介导的。通过 PET 测量的这种纵向 tau 积累伴随着脑萎缩和临床下降。我们的结果表明，APOEε4 等位基因在 Aβ 对人脑中磷酸化 tau 聚集的下游效应中起着关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64b0/10592050/f76c00d0a0ea/nihms-1928981-f0004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64b0/10592050/e926e8132a45/nihms-1928981-f0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64b0/10592050/b5aadd76a027/nihms-1928981-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64b0/10592050/91ef4284c11e/nihms-1928981-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64b0/10592050/97bd088bcc21/nihms-1928981-f0002.jpg
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