Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Annalise Noelle VonderEmbse (Creator)
East Carolina University (ECU )
Web Site: http://www.ecu.edu/lib/

Abstract: The association between perturbations to neuroimmune development and susceptibility to adult neurodegenerative diseases , like Alzheimer's disease (AD) , may undersore a putative pathogenic role for gradual microglial dysfunction. In the present thesis , gene and environment (GxE) interactions were evaluated in the propagation of microglial dysfunction within the context of AD. We hypothesized that postnatal toxicant exposure in a mouse model of AD (Tg) would disrupt neuroimmune development preferentially in females , in parallel with human AD sex bias , incurring altered regulation of microglial response phenotypes early in life that then functionally persists as the reduced capacity to adapt later in life , thereby promoting synaptic dysfunction and increasing susceptibility to AD. Following postnatal exposure to lead acetate (Pb) from postnatal day (PND) 5-15 , earlier and more severe amyloid accumulation was observed in the hippocampus concomitant to reduced microglial activation (densitometric Iba1+ , CD45lo/CD11b+ characterization) in females compared to males by PND 50 , inferring that non-neuroprotective microglia exacerbated AD susceptibility with female bias. In order to determine the extent of microglial dysfunction at the level of the synapse , deficits in neuroprotective capabilities , such as microglial ferritin expression and polarization profiles (CD86:CD209) , in the amyloid-stressed environment of older animals were investigated following a similar exposure period to Pb from PND 5-10. Congruent with our previous findings , Pb-exposed Tg females preferentially exhibited gross abnormalities in healthy microglia:neuron signaling , such as atypical TrkB expression in the CA3 region , that transitioned to maladaptive over time. The addition of a wildtype (WT) mouse comparison substantiated the selective GxE synergism in microglial maladaptation , prompting investigation for early epigenetic regulation for a dysfunctional phenotype of susceptibility that could persist into adulthood. As hypothesized , deleterious expression patterns for miR-124 , miR-132 , and miR-34a , critical to homeostatic neuroimmune maturation , were observed in Pb-exposed Tg females by PND 10 and 21 , suggesting persistent , epigenetic re-patterning of the microglial response phenotype and limited adaptability. The results presented in this thesis converge to describe a newly established critical window of postnatal developmental sensitivity for female-specific microglial maladaptation. Collectively , this set of experiments provides insight into the potentiative effects of GxE during development and neuroimmune-related susceptibility to AD.

Additional Information

Language: English
Date: 2017
developmental immunotoxicity, developmental origins of adult disease

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Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicityhttp://hdl.handle.net/10342/6370The described resource references, cites, or otherwise points to the related resource.