Abstract
The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na+-K+-2Cl− cotransporter 1 (NKCC1) and neuronal K+-Cl− cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission.
Highlights
The amyloid precursor protein (APP) is critically involved in the pathophysiology of Alzheimer’s disease (AD)[1], the most prevalent cause of dementia affecting more than 44 million people worldwide
Taken together the results suggest that GABA is more depolarizing in human APP (hAPP) expressing neurons, which could be due to a modification in [Cl−]i levels resulting from a decrease in K+-Cl− cotransporter 2 (KCC2) expression in these cells
Several lines of evidence coming from mice overexpressing or lacking APP indicate that APP could play a role in GABAergic neurotransmission[10,11,12,13,14,15, 55]
Summary
The amyloid precursor protein (APP) is critically involved in the pathophysiology of Alzheimer’s disease (AD)[1], the most prevalent cause of dementia affecting more than 44 million people worldwide (from World Alzheimer Report 2015). Changes in NKCC1 and KCC2 expression levels influence the polarity of inhibitory currents mediated by GABA or glycine, another inhibitory neurotransmitter. Increased KCC2 expression levels lead to an increase in Cl− extrusion, a reduction in [Cl-]i and subsequent conversion of inhibitory neurotransmission from depolarizing to hyperpolarizing[27]. In a mouse model of Down syndrome (DS), where APP is overexpressed, dysregulation of cation Cl− cotransporters expression leads to excitatory GABAAR signaling[29]. These DS mice carry an extra copy of mouse chromosome 16 syntenic to the long arm of human chromosome 2130 containing the human APP gene[31].
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