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vonderEmbse et al. Neuroimmunol Neuroinflammation 2020;7:345-59 I http://dx.doi.org/10.20517/2347-8659.2019.29 Page 347

of homeostatic baselines, immune maturation and learning, and even patterns of functional response
phenotypes. MicroRNA expression patterns are both evidentiary of past exogenous influences and
predictive of future cellular response, such that altered miRNAs promoting the disjointed development
of microglia and neurons early in life may impact the intertwined functionality of neuroimmune cells
[25]
throughout life. MicroRNAs are highly involved in central nervous system development and, more
pertinently, the promotion of varied microglial states of activation and quiescence and the dynamic
[26]
transitions therein . Notably, a cluster of microRNAs referred to as “NeurimmiRs” have been described
in modulating both neuronal and immune processes, such a miR-124 and miR-132, that act as negotiators
[27]
at the neuroimmune interface . The most abundant microRNA expressed in the adult brain, miR-124
exhibits highly conserved expression patterns consistent with a critical role in neurodevelopment and
neurogenesis [25,28] . The expression of miR-124 has also been shown to promote microglial quiescence
transitioning from an activated amoeboid state through the downregulation of M1-associated markers [26,29] .
Likewise, miR-132 is involved in the regulation of neurotransmission and synaptogenesis and is upregulated
during postnatal development . Correspondingly, both miR-124 and miR-132 are downregulated
[27]
[32]
in the brains of patients with AD [30,31] . Although a recent report by Gillet et al. underscored how
certain neurodevelopmental disorders were correlated with altered microRNA expression from toxicant
exposures, there is still a disconnect with etiopathological relevance in DOAD models for aging-related
neurodegenerative diseases like AD. Furthermore, while microRNAs are persistently modified due to
[33]
early-life Pb exposure , there is a little characterization of the sexually dimorphic effects in Pb-altered
epigenetic profiles related to neuroimmune function.

Both rodent and human brains undergo sexually dimorphic neuroimmune development, specifically within
the postnatal period, during which PGE2 secreted by microglia critically regulates the masculinization
[34]
of the male brain . Blocking PGE2 with the NSAID indomethacin (indo) resulted in a “feminization” of
male microglia, significantly reducing the number of amoeboid, but not total, microglia in the preoptic
[35]
area of 2-day-old male mice . Importantly, the number and phenotype of microglia at varying time points
and brain regions varies dramatically by sex throughout development; a spike in the number of amoeboid
microglia in males parallels a testosterone surge at PND 4, whereas amoeboid microglia numbers within
[36]
specific brain regions don’t peak in female brains until PND 30 . Thus, the transition from DAP12-
positive immature amoeboid phenotypes to fully mature, ramified microglia occurs earlier in males than
females. Previously, the first two postnatal weeks were generally considered a period of male-specific
[37]
microglial vulnerability to later-life immune-related priming , but, here, we report a comparable postnatal
window of female-specific microglial and neuronal vulnerability to epigenetic regulation in a GxE model
for AD. Nearly 2/3rds of the 250 miRNAs surveyed in neonatal mouse brains by Morgan and Bale
[38]
were shown to be differentially expressed in males and females, implicating miRNAs as major epigenetic
regulators of sex differences in the developing brain [39,40] . In the current study, miR-34a was also evaluated
alongside the neurimmiRs miR-124 and miR-132, given reports that the upregulation of miR-34a decreased
TREM2 expression by targeting parts of its mRNA . Furthermore, expression of miR-34a both strongly
[41]
[42]
promotes and is itself promoted by, p53 as a cellular stress response leading to apoptosis and senescence ,
and modifications to this microRNA may suggest the presence of cellular stress signals that are readily
detectable by microglia. Interestingly, mutations to presenilin2, one of the genes implicated in familial AD,
[43]
has been shown to trigger neuronal apoptosis via the miR-34a/p53 axis . Likewise, TP53, the “apoptosis
[42]
gene” that encodes for p53, is mutated in some cases of AD .
The present study aimed to delineate the early epigenetic regulation of neuroimmune phenotypes related to
the promotion of lifelong homeostatic microglia: neuron signaling as a consequence of toxicant exposure.
The adaptive response of immune cells to fine-tune signaling in homeostatic pathways is not only critical
in adulthood but defined during development. Thus, we hypothesized that the combination of a genetic
proclivity to AD and postnatal exposure to Pb would result in persistent, differential changes in interrelated