Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction

被引：181

作者：

Lopez-Rodriguez, Ana Belen ^{[1
,2
]}

Hennessy, Edel ^{[1
,2
]}

Murray, Carol L. ^{[1
,2
]}

Nazmi, Arshed ^{[1
,2
]}

Delaney, Hugh J. ^{[1
,2
,3
]}

Healy, Daire ^{[1
,2
]}

Fagan, Steven G. ^{[1
,2
]}

Rooney, Michael ^{[1
,2
]}

Stewart, Erika ^{[1
,2
]}

Lewis, Anouchka ^{[1
,2
]}

de Barra, Niamh ^{[1
,2
]}

Scarry, Philip ^{[1
,2
]}

Riggs-Miller, Louise ^{[1
,2
]}

Boche, Delphine ^{[4
]}

Cunningham, Mark O. ^{[3
]}

Cunningham, Colm ^{[1
,2
]}

机构：

[1] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin, Ireland

[2] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Dublin, Ireland

[3] Trinity Coll Dublin, Sch Med, Discipline Physiol, Dublin, Ireland

[4] Univ Southampton, Fac Med, Clin Neurosci Clin & Expt Sci Acad Unit, Southampton, Hants, England

来源：

ALZHEIMERS & DEMENTIA | 2021年 / 17卷 / 10期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

APP/PS1; astrocyte; CCL2; chemokine; cytokine; delirium; dementia; gamma; IL-1; beta; memory; microglia; network dysfunction; neuroinflammation; primed; priming; vulnerability; COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID; HIP FRACTURE; GENE-EXPRESSION; MOUSE MODELS; POSTOPERATIVE DELIRIUM; TAU PATHOLOGY; MICROGLIA; INTERLEUKIN-1-BETA; DECLINE;

D O I：

10.1002/alz.12341

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1 beta (IL-1 beta) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1 beta. Systemic LPS triggered microglial IL-1 beta, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1 beta disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1 beta and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

引用

页码：1735 / 1755

页数：21

共 106 条

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