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

Abstract

BackgroundAlzheimer’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.MethodsThe 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.ResultsWe 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.ConclusionChronic 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.

Deciphering the mechanism underlying late-onset Alzheimer disease

“…16 More recently, we demonstrated that upon second immune stimulation with PolyI:C in adulthood, prenatally challenged animals developed an AD-like pheno type. 17 The ageing-associated progression of disease in these mice was in striking similarity to that described in patients with AD. 2 In addition, systemic immune challenge in adult transgenic AD mice led to a strong aggravation of the AD-like pathology, 17 in agreement with the observation that both acute and chronic inflammation are associated with an increase in cognitive decline in patients with AD.…”

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…In support of such a view is the observation that upon neuronal injury, Reelin expression is up regulated in Schwann cells (Panteri et al, 2006) and that Reelin knock-out mice show impaired peripheral nerve regeneration (Lorenzetto et al, 2008). It would be highly relevant, therefore, to check in the adult brain if oligodendrocytes, which express Reelin in vitro (Siebert and Osterhout, 2011) Importantly, we were recently able to demonstrate that a viral-like prenatal immune challenge predisposes the offspring to develop an AD-like phenotype, which is induced if the challenge is repeated for a second time during adulthood (Krstic et al, 2012a). In these prenatally challenged mice, the loss of Reelin expressing cells (Meyer et al, 2008, Knuesel et al, 2009 coincided with an increase in APP production and cleavage, Tau hyperphosphorylation and missorting, as well as cognitive deficits (Krstic et al, 2012a).…”

“…It would be highly relevant, therefore, to check in the adult brain if oligodendrocytes, which express Reelin in vitro (Siebert and Osterhout, 2011) Importantly, we were recently able to demonstrate that a viral-like prenatal immune challenge predisposes the offspring to develop an AD-like phenotype, which is induced if the challenge is repeated for a second time during adulthood (Krstic et al, 2012a). In these prenatally challenged mice, the loss of Reelin expressing cells (Meyer et al, 2008, Knuesel et al, 2009 coincided with an increase in APP production and cleavage, Tau hyperphosphorylation and missorting, as well as cognitive deficits (Krstic et al, 2012a). This is in agreement with the observations of cognitive decline in aged rats correlating with reduced Reelin expression in the entorhinal cortex (Stranahan et al, 2011a), recently confirmed by the findings of impaired spatial memory following experimental interference with Reelin signaling in the same area (Stranahan et al, 2011b).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Although the majority of inflammation in AD is attributed to glia dysfunction, especially in microglia and astrocytes, systemic inflammation shows a strong association with AD, as shown by an interesting experiment: Under systemic immune challenge by the viral mimic polyriboinosinic–polyribocytidilic acid, mice show sporadic AD phenotypes including Aβ plaques and altered Tau phosphorylation (Krstic et al, 2012). In human, there are some similar association studies: Obesity increases the likelihood of systemic inflammation (Almond, Edwards, Barclay, & Johnston, 2013), and white‐fat tissue has a high percentage of activated macrophages secreting proinflammatory cytokines (Bastard et al, 2006); thus, it is not surprising to find that midlife obesity is a risk factor for AD (Whitmer et al, 2008).…”