title: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.
abstract: 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 inflammation 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, 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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
authors: Dimitrije
authors: D
authors: Krstic
authors: Amrita
authors: A
authors: Madhusudan
authors: Jana
authors: J
authors: Doehner
authors: Prisca
authors: P
authors: Vogel
authors: Tina
authors: T
authors: Notter
authors: Claudine
authors: C
authors: Imhof
authors: Abigail
authors: A
authors: Manalastas
authors: Martina
authors: M
authors: Hilfiker
authors: Sandra
authors: S
authors: Pfister
authors: Cornelia
authors: C
authors: Schwerdel
authors: Carsten
authors: C
authors: Riether
authors: Urs
authors: U
authors: Meyer
authors: Irene
authors: I
authors: Knuesel
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011070:Poly I-C / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*
chemical_list: D011070:Poly I-C