Litigation Against Physicians Caring for Collegiate Athletes in the United States.

MicroRNAs (miRNAs) are short, 21‐ to 23‐nucleotide, single‐stranded, non‐coding RNA molecules. They bind most commonly to the 3'UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA, cleavage of the mRNA strand, and translational silencing. In mammalian brains, miRNA expression profiles are cell‐type‐specific,, with distinct functions and roles across different neural subtypes, influencing both brain development and susceptibility to neurological disorders.,
is a multifunctional miRNA first described as a central player in the macrophage inflammatory response and then extensively studied as a microglial master regulator in neuroinflammation in neurodegenerative conditions, including Alzheimer's disease (AD). Recent studies, including some from our laboratory, demonstrated that is upregulated in the hippocampal neurons of AD patients and in mouse models of AD pathology., , Other studies have focused on the increase of as part of Trisomy 21 in Down syndrome (DS) patients showing impaired neurogenesis and synaptogenesis during human brain development that is also manifested in cortical neurons derived from DS patient human induced pluripotent stem cells (hiPSCs), and in the Ts65Dn mouse model of DS. The hippocampus plays an essential role in human cognition and memory and is severely affected in AD. Hippocampal neurogenesis contributes to hippocampal plasticity through the integration of new neurons into existing circuits. Hippocampal neurogenesis in rodents involves radial glia‐like neural stem cells (RGL‐NSCs) in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), which generate proliferating intermediate progenitor cells (IPCs) and neuroblasts that differentiate into dentate granule neurons. Markers of hippocampal neurogenesis decline sharply in AD., Hippocampal GABA(gamma‐aminobutyric acid)ergic interneurons primarily originate from the ventral telencephalon, and their generation and specification are governed by transcription factors such as NR2F1/2., They represent 10% to 15% of the total neuronal population and serve as major determinants of virtually all aspects of cortical circuit function. Parvalbumin (PV) and somatostatin (SST) subtypes comprise ∼70% of inhibitory GABAergic interneurons., In AD, there are significant reductions in levels of GABA and somatostatin in the cerebrospinal fluid (CSF) and brain., , Single‐cell RNA sequencing (RNA‐seq) studies confirmed the selective depletion of PV‐ and SST‐positive GABAergic inhibitory neurons., To determine whether miR155 overexpression individually contributed to the changes described above, we utilized (1) in silico analyses of published databases to show the relationship in three‐dimensional (3D) chromatin structure between transcription of and ; (2) newly generated ‐deleted hiPSCs using CRISPR/Cas9 genome editing technology to produce NSCs, cortical and GABAergic neurons, and cortical organoids; (3) lentivirus‐mediated ‐overexpressing hiPSC‐derived NSCs and cortical and GABAergic neurons; and (4) KO mice to compare and contrast the effects of decreased in vitro and in vivo. Integration of data from these systems supports a novel role for in the regulation of interneuron numbers and phenotypes highly relevant to AD and DS, likely dependent on NR2F1 and NR2F2. Taken together, our findings suggest distinct cell‐type‐specific roles of in GABAergic interneurons in the pathogenesis of AD. This raises the possibility that therapeutic modulation of in both neurons and microglia might be beneficial in the treatment and/or prevention of AD, but the cell‐type‐specific valence creates a unique challenge, as altering expression in either direction or at different stages of disease could be harmful in one cell type while being protective in another.