Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain

Abstract

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Calcineurin: directing the damage in Alzheimer disease

“… Increasing evidence suggests that the protein phosphatase calcineurin (CN) mediates or exacerbates Alzheimer disease (AD) pathophysiology through activation of the NFAT family of transcription factors. In this editorial, we discuss work by Hopp et al ., , which uncovered a novel role of CN/NFAT signaling in controlling global gene expression in hippocampal neurons of intact mice. Interestingly, the authors showed that elevated CN expression/activity in neurons plays a major role in transcriptional suppression.…”

“…In this issue of the Journal of Neurochemistry , Hopp et al . () provide significant insight into how CN/NFAT signaling can contribute to AD pathophysiology through the shaping of transcriptional programs in neurons. Previous work from this group elegantly showed that aberrant neuronal CN/NFAT signaling underlies neurite atrophy and synapse loss in response to pathogenic oligomeric β‐amyloid peptides (Kuchibhotla et al, Hudry et al .…”

“…Hopp et al . () therefore predicted that neuronal CN hyperactivity in intact wild‐type mice would partially recapitulate AD‐related gene expression programs linked to synapse integrity and function.…”

“…Many putative NFAT sensitive genes were also identified by Hopp et al . (), as were a number of micoRNA‐regulated gene pathways, suggesting that CN represses neuronal gene expression, in part, through NFAT and microRNA‐dependent mechanisms. As synapse loss represents a proximal cause for cognitive dysfunction, the work by Hopp et al .…”

“…As synapse loss represents a proximal cause for cognitive dysfunction, the work by Hopp et al . () provides a potentially very important piece of the puzzle as to how neuronal Ca 2+ dysregulation leads to disrupted neural circuitry and the progressive clinical symptoms of AD.…”