p75NTR enhances cognitive dysfunction in a mouse Alzheimer's disease model by inhibiting microRNA-210-3p-mediated PCYT2 through activation of NF-ΚB

Alzheimer's disease (AD) is a main cause of dementia and exhibits abnormality in cognitive behaviors. Here, we probed into the role of p75 neurotrophin receptor (p75NTR) in cognitive dysfunction in AD. Primarily, C57BL/6 mouse and neuroblastoma cells were treated by amyloid-beta1-42 (A beta 1-42), respectively, to establish the in vivo and in vitro models of AD. The downstream genes of p75NTR were predicted by RNA-sequencing and bioin-formatics analysis. Then the interaction among p75NTR, nuclear factor kappa B (NF-kappa B), microRNA-210-3p (miR-210-3p) and phosphoethanolamine cytidylyltransferase 2 (PYCT2) was verified, followed by analysis of their effects on cognitive behaviors and biological characteristics of hippocampal neurons of mouse with AD-like symptoms. p75NTR knockout alleviated cognitive dysfunction in mice with AD-like symptoms and reduced A beta 1-42-induced hippocampal neuron damage and apoptosis. p75NTR up-regulated miR-210-3p expression by activating NF-kappa B, thereby limiting PCYT2 expression. PCYT2 silencing in p75NTR- /-mice promoted neuronal apoptosis and aggravated cognitive dysfunction in AD mouse models. In summary, p75NTR is capable of accelerating cognitive dysfunction in AD by mediating the NF-kappa B/miR-210-3p/PCYT2 axis.

Automated summary

This study investigated the role of p75 neurotrophin receptor (p75NTR) in cognitive dysfunction in Alzheimer's disease (AD). In vivo and in vitro models of AD were established using C57BL/6 mice and neuroblastoma cells treated with amyloid-beta1-42 (Aβ1-42), respectively. RNA-sequencing and bioinformatics analysis predicted the downstream genes of p75NTR. The interaction between p75NTR, nuclear factor kappa B (NF-κB), microRNA-210-3p (miR-210-3p), and phosphoethanolamine cytidylyltransferase 2 (PYCT2) was verified, and their effects on cognitive behaviors and biological characteristics of hippocampal neurons in AD mouse models were analyzed. p75NTR knockout alleviated cognitive dysfunction and reduced hippocampal neuron damage and apoptosis in AD-like mice. p75NTR upregulated miR-210-3p expression by activating NF-κB, thereby limiting PCYT2 expression. PCYT2 silencing in p75NTR-/- mice promoted neuronal apoptosis and aggravated cognitive dysfunction in AD mouse models. In summary, p75NTR accelerates cognitive dysfunction in AD through the NF-κB/miR-210-3p/PCYT2 axis.