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Dysfunctional microglia:neuron interactions with significant female bias in a developmental gene x environment rodent model of Alzheimer's disease.

08:00 EDT 27th March 2019 | BioPortfolio

Summary of "Dysfunctional microglia:neuron interactions with significant female bias in a developmental gene x environment rodent model of Alzheimer's disease."

Signaling between microglia and neurons is poorly characterized in the pathophysiology of Alzheimer's disease (AD), particularly with regards to gene and environmental (GxE) interactions early in life. This study investigated the maladaptation of microglia:neuron signaling and subsequent susceptibility to neurodegeneration using a developmental origin of adult disease (DOAD) model of AD, characterized previously. Here, we report that postnatal exposure to lead (Pb) in a transgenic (Tg) rodent model of AD resulted in significant female bias consequent to GxE interactions. Atypical, non-neuroprotective microglial phenotypes were observed months after cessation of Pb exposure, as well as evidence for neuronal compensation, that was not observed in WT mice. Specifically, microglia from Pb-exposed Tg (GxE) females exhibited atypical polarization profiles for activation earlier and more severely than males and WT mice, that persisted over time to become contextually maladaptive. By postnatal day (PND) 240, microglia from GxE females also sequestered less neurotoxic iron in the hippocampus. In the same GxE female population, measures of neuronal parameters, such as hippocampal TrkB expression, revealed evidence of disharmonious and compensatory interactions with microglia within the pathological progression. Likewise, GxE interactions resulted in female-biased, late-life changes to key synaptic proteins crucial to synapse dynamics and microglial signaling. These incongruent microglia:neuronal dynamics were observed in GxE males at later ages compared to females, and not observed in either gene- or environment-only populations. Altogether, our results support a gene x environment model of female-biased microglial susceptibility to later-life development of AD, and highlight markers for maladaptive microglia:neuron signaling and compensation.

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This article was published in the following journal.

Name: International immunopharmacology
ISSN: 1878-1705
Pages: 241-250

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