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Wissenschaftliche Ergebnisse der Deutschen Tiefsee-Expedition auf der Dampfer "Valdivia" 1898-1899 : im auftrage des Riechsamtes des Innern / herausgegeben von Carl Chun.

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.

Journal of neuroinflammation, 2012-07, Vol.9 (1), p.151-151, Article 151

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

As research into various aging-associated neurodegenerative disorders reveals their immense pathophysiological complexity, the focus is currently shifting from studying changes in an advanced disease state to investigations involving pre-symptomatic periods, possible aberrations in early life, and even abnormalities in brain development. Recent studies on the etiology of schizophrenia and autism spectrum disorders revealed a profound impact of neurodevelopmental disturbances on disease predisposition, onset and progression. Here, we discuss how a prenatal immune challenge can affect the developing brain—with a selective focus on the impact on microglia, the brain’s immune cells—and the implications for brain aging and its associated risk of developing Alzheimer’s disease.

Journal of neuroimmune pharmacology, 2013-03, Vol.8 (1), p.79-86

Impact of Prenatal Immune System Disturbances on Brain Development

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Wissenschaftliche Ergebnisse der Deutschen Tiefsee-Expedition auf der Dampfer "Valdivia" 1898-1899 : im auftrage des Riechsamtes des Innern / herausgegeben von Carl Chun.

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

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Impact of Prenatal Immune System Disturbances on Brain Development

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Export record to excel

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Wissenschaftliche Ergebnisse der Deutschen Tiefsee-Expedition auf der Dampfer "Valdivia" 1898-1899 : im auftrage des Riechsamtes des Innern / herausgegeben von Carl Chun.

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

Export this record

Export record to excel

Impact of Prenatal Immune System Disturbances on Brain Development

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