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Page 346 vonderEmbse et al. Neuroimmunol Neuroinflammation 2020;7:345-59 I http://dx.doi.org/10.20517/2347-8659.2019.29

Conclusion: This study demonstrates the exacerbating effects and early manifestation of GxE interactions in
this model. Furthermore, these findings underscore a period of female-specific vulnerability to epigenetic
maladaptation during postnatal development, with implications on the faulty later-life adaptability of neuroimmune
signaling. Further investigation is warranted to evaluate the persistence and relative contribution of these early
influences on the etiopathology of Alzheimer’s disease.

Keywords: MicroRNA, microglia, Alzheimer’s disease, developmental origins of adult disease

INTRODUCTION
Numerous studies examining the developmental origins of adult disease (DOAD) hypothesis have
shown that environmental perturbations to neuroimmune development may contribute to later-life
[1-3]
neurodegenerative diseases, like Alzheimer’s disease (AD) . The consequence of gene x environment (GxE)
interactions is much more profound during development due to critical windows in which phenotypic
plasticity is instructed by, and extremely sensitive to, exogenous signaling. In our previous studies using a
DOAD model for AD, we reported that the interaction of GxE exacerbated AD susceptibility later in life in
[4,5]
a transgenic AD mouse model postnatally exposed to lead acetate (Pb) . This GxE-related vulnerability
was concurrent with dysfunctional microglial phenotypes and synaptic defects indicative of atypical
microglia-neuron interactions, and significantly biased towards females. In agreement with the literature,
microglia in aging brains can become senescent, dystrophic, and mount ineffective or inappropriate
[6-8]
responses to neuronal signaling . Importantly, the spatially- and temporally-synchronized development
of microglia and neurons during the perinatal period fine-tunes this crosstalk necessary for homeostatic
[9]
signaling in the adult . Thus, imbalances in neuroimmune signaling and function may be developmentally
promoted.

Healthy homeostatic interactions between microglia and neurons in adulthood depend on the tightly-
[9]
controlled developmental programming of microglia in response to cues from neurons , clearly
demonstrated in studies of early immune insults resulting in cognitive decline, impaired memory, and
even neurodegeneration in adulthood [2,10-13] . Mutations to the transmembrane adaptor protein DAP12 or its
[14]
ligand TREM2 are associated with a form of presenile dementia called Nasu-Hakola disease in humans ,
and patients with heterozygous variants of TREM2 have a significantly higher susceptibility to AD [15-17] .
Furthermore, the typical expression of DAP12 is limited to perinatal microglia and is critical for healthy
developmental synaptic pruning by microglia [18,19] . DAP12-deficient rodent models exhibit persistent
synaptic defects to glutamatergic synapses in adulthood [20,21] . Therefore, DAP12 may highlight a particular
junction of the neuroimmune interface during development by which microglia and neurons establish and
promote healthy synapse dynamics throughout life, with implications for the promotion of early AD-like
phenotypes in its absence. However, little is known about the molecular mechanisms through which early-
life toxicant exposure alters this junction to promote atypical signaling between neurons and microglia that
then persist beyond development.

As environmentally sensitive genomic regulators, microRNAs represent a form of long-term epigenetic
regulation relevant to GxE studies to fine-tune cellular phenotypes. Nearly 60% of all protein-encoding
genes are thought to be regulated by miRNAs , and, with half-lives nearly 10x longer than mRNA ,
[22]
[23]
numerous studies have already begun exploring the potential of these molecules to act as biomarkers of
disease . In the healthy adult brain, transient changes to miRNAs are often the result of the immediate
[24]
microenvironment, promoting functional changes to parenchymal targets as a cellular adaption to
exogenous influences - temporarily shifting the requirements for homeostasis. However, altered miRNAs
during critical windows of neuroimmune development have direct consequences on the promotion