JNI：大脑慢性炎症导致阿尔茨海默氏症

今天发表在BioMed Central开放期刊Journal of Neuroinflammation杂志上的一则研究表明，大脑慢性炎症会引发阿尔茨海默氏症。

迄今为止，阿尔茨海默氏病（AD）与炎症之间的相关关系一直得不到很好的阐述，最近研究结果表明，非甾体抗炎药可以在疾病早期阶段帮助AD患者，但想要得到确切的效益，需长期治疗。

苏黎世ETH与伯尔尼大学研究人员合作研究了什么样的免疫系统会对AD小鼠疾病发展有影响。结果表明出生前存在感染的小鼠足以引发长期的老年神经系统变化以及显著的记忆问题。

这些老鼠炎性细胞因子水平的提高，导致淀粉样前体蛋白（APP）的水平增加，改变Tau蛋白的细胞定位。这提示慢性炎症可能是一个AD发展的早期事件。

doi:10.1186/1742-2094-9-151

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Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

Dimitrije Krstic, Amrita Madhusudan, Jana Doehner, Prisca Vogel, Tina Notter, Claudine Imhof, Abigail Manalastas, Martina Hilfiker, Sandra Pfister, Cornelia Schwerdel, Carsten Riether, Urs Meyer and Irene Knuesel

Background

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 infection or neuroinflammation and the onset of the disease.

Methods

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.

Results

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, its 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 Abeta 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.

Conclusion

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 Abeta 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.