Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.
Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.
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DOI：
10.1186/1742-2094-9-151
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发表时间：
2012-07-02
影响因子：
9.3
通讯作者：
Knuesel I
中科院分区：
文献类型：
--
作者：
Krstic D;Madhusudan A;Doehner J;Vogel P;Notter T;Imhof C;Manalastas A;Hilfiker M;Pfister S;Schwerdel C;Riether C;Meyer U;Knuesel I
阿尔茨海默病（AD）是最普遍的年龄相关性痴呆形式，并且其对社会的影响随着人口老龄化呈指数级增加。越来越多的证据表明，由大脑先天免疫系统介导的神经炎症有助于AD神经病理学并加剧疾病的进程。然而，没有实验证据表明全身炎症或神经炎症与疾病发作之间存在因果关系。病毒模拟物，聚核糖肌苷-聚核糖胞苷酸（PolyI：C）被用来刺激实验动物的免疫系统。将野生型（WT）和转基因小鼠在产前（妊娠第17天（GD））和/或成年期暴露于该细胞因子诱导剂。行为学，免疫学，免疫组化和生化分析的AD相关的神经病理变化进行老化。我们发现，在妊娠晚期的全身免疫挑战，易使WT小鼠在衰老过程中发展AD样神经病理学。它们显示炎性细胞因子的慢性升高，海马淀粉样前体蛋白（APP）及其蛋白水解片段水平的增加，Tau磷酸化改变，以及体树突区室的错误分类，以及老年工作记忆的显著损害。如果这种产前感染之后是成年后的第二次免疫攻击，则表型强烈恶化，并模仿AD样神经病理学变化。这些包括APP及其蛋白水解片段的沉积，沿着Tau聚集、小胶质细胞活化和反应性神经胶质增生。尽管在15个月时，双重免疫激发的WT小鼠的细胞外沉积物中Aβ肽没有显著富集，但在年龄匹配的免疫激发的转基因AD小鼠中，Aβ肽显著增加，精确地在炎症诱导的APP及其蛋白水解片段积聚周围，与AD患者的尸检结果惊人相似。慢性炎症性疾病诱导WT小鼠中AD样表型的年龄相关性发展，包括诱导APP积累，这代表了易于聚集的肽沉积的种子。因此，PolyI：C小鼠模型提供了一种独特的工具，用于研究衰老生理背景下神经元Aβ斑块沉积和神经元缠结形成之前最早期病理生理学变化的分子机制。基于免疫攻击小鼠的变化与人类AD发展之间的相似性，我们认为全身感染是AD发展的主要风险因素。
Alzheimer’s disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain’s innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease. The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.
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影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
6.1
作者：
Edison, Paul;Archer, Hilary A.;Brooks, David J.
通讯作者：
Brooks, David J.
DOI：
10.1016/j.jalz.2010.12.014
发表时间：
2011-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Breitner JC;Baker LD;Montine TJ;Meinert CL;Lyketsos CG;Ashe KH;Brandt J;Craft S;Evans DE;Green RC;Ismail MS;Martin BK;Mullan MJ;Sabbagh M;Tariot PN;ADAPT Research Group
通讯作者：
ADAPT Research Group
影响因子：
3.4
作者：
Anisman, Hymie;Gibb, Julie;Hayley, Shawn
通讯作者：
Hayley, Shawn