Several of their multiple AD-relevant mRNA targets, the function of those mRNAs and consequences of their deficits, and original key references are shown. As indicated, inducible miRNA-125b and miRNA-146a have experimentally verified mRNA targets including the glial cell cycle and glial cell proliferation inhibitor cyclin-dependent kinase 2A (CDKN2A), the neurotransmitter ATPase release and synaptic protein SYN-2, the essential docosahexaenoic acid-to-neuroprotectin D1 (NPD1) conversion enzyme 15-LOX (also known as ALOX15), the innate immune system regulator CFH, IRAK-1 and the ??APP-disintegrin and metalloproteinase-10 regulatory protein TSPAN12 [3,57-82]. These combined data suggest a complex and highly interactive role for NF-??B, miRNA-125b and miRNA-146a in physiologically stressed HNG cells in primary co-culture.

Remarkably, the misregulation of just two NF-??B-regulated, proinflammatory miRNAs has the potential to contribute to the deregulation of several key features of AD neuropathology, including neurotrophic support, synaptogenesis, neuroinflammation, innate immune signaling, and amyloidogenesis in primary human neural cells. Importantly, upregulation of miRNA-125b and miRNA-146a has been observed in anatomical areas of the brain targeted by the AD process, but neither in unaffected regions of the same brain, such as the brain stem or thalamus, nor in the same anatomical areas in healthy age-matched controls [57,74,83]. More recently, interrelated and independent studies further suggest the sensitivity of human miRNA-9, miRNA-34a and miRNA-155 to AD-relevant stress and neuropathology as NF-??B-mediated miRNAs (Figure ?(Figure1)1) [38,40,45,59,74,83].

While the neurological activities of miRNA-9, miRNA-34a and miRNA-155 are currently under active investigation by multiple laboratories, miRNA-125b and miRNA-146a and several of their mRNA targets, and the implications, are further discussed in the following sections. miRNA-125b One of the most human brain cell-abundant miRNAs, if not the most abundant CNS miRNA, is inducible miRNA-125b [23,45,49,51,55,57,58,83-87]. This extensively studied 22-nucleotide miRNA (encoded at human chromosome 11q24.1: 5′-ucccugagacccuaacuuguga-3′ [Genbank:"type":"entrez-nucleotide","attrs":"text":"NR_029671.1","term_id":"262205263","term_text":"NR_029671.1"NR_029671.

1]) was first shown to be upregulated in both stressed and differentiating mouse and human neurons, and has since been implicated in mammalian neuronal development, brain cell signaling functions and degenerative disease [45,49]. NF-??B-regulated proinflammatory miRNA-125b has been further shown to be induced GSK-3 by human neurotrophic viruses and by neurotoxic metal sulfates, such as aluminum sellectchem sulfate, that generate robust oxidative stress and ROS in human brain cells [83-101].