APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread

被引：57

作者：

Chen, Yun ^{[1
,2
]}

Song, Sihui ^{[1
]}

Parhizkar, Samira ^{[1
,4
]}

Lord, Jennifer ^{[1
]}

Zhu, Yiyang ^{[1
]}

Strickland, Michael R. ^{[1
]}

Wang, Chanung ^{[1
]}

Park, Jiyu ^{[1
]}

Tabor, G. Travis ^{[1
]}

Jiang, Hong ^{[1
,3
,4
]}

Li, Kevin ^{[1
]}

Davis, Albert A. ^{[1
,3
]}

Yuede, Carla M. ^{[1
,3
,4
,5
,6
]}

Colonna, Marco ^{[2
,3
]}

Ulrich, Jason D. ^{[1
,3
,4
]}

Holtzman, David M. ^{[1
,3
,4
]}

机构：

[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO 63110 USA

来源：

CELL | 2024年 / 187卷 / 02期

基金：

美国国家卫生研究院;

关键词：

HUMAN APOLIPOPROTEIN-E; AMYLOID-BETA; ALZHEIMER-DISEASE; III HYPERLIPOPROTEINEMIA; PATHOGENESIS; PROPAGATION; PATHOLOGY; VARIANTS; PATIENT; BINDING;

D O I：

10.1016/j.cell.2023.11.029

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock -in mouse and crossed it to an amyloid-D (AD) plaque -depositing model. We injected AD -tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque -associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to AD plaques, which suppresses AD -induced tau seeding and spreading. The results reveal new possibilities to target AD -induced tauopathy.

引用

页码：428 / 445.e20

页数：39

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