Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity
VonderEmbse, Annalise Noelle
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.
VonderEmbse, Annalise Noelle. (July 2017). Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6370.)
VonderEmbse, Annalise Noelle. Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity. Doctoral Dissertation. East Carolina University, July 2017. The Scholarship. http://hdl.handle.net/10342/6370. September 26, 2020.
VonderEmbse, Annalise Noelle, “Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity” (Doctoral Dissertation., East Carolina University, July 2017).
VonderEmbse, Annalise Noelle. Microglial dysfunction as an early susceptibility to Alzheimer's disease: the exacerbating role of developmental toxicity [Doctoral Dissertation]. Greenville, NC: East Carolina University; July 2017.
East Carolina University