Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor.

Andrew Speidell,Gino Paolo Asuni,Patrick Forcelli,Serena Scognamiglio,Italo Mocchetti,Valeria Avdoshina

doi:10.3389/fncel.2019.00398

Abstract

Activation of the p75 neurotrophin receptor (p75NTR), by the proneurotrophin brain-derived neurotrophic factor (proBDNF), triggers loss of synapses and promotes neuronal death. These pathological features are also caused by the human immunodeficiency virus-1 (HIV) envelope protein gp120, which increases the levels of proBDNF. To establish whether p75NTR plays a role in gp120-mediated neurite pruning, we exposed primary cultures of cortical neurons from p75NTR–/– mice to gp120. We found that the lack of p75NTR expression significantly reduced gp120-mediated neuronal cell death. To determine whether knocking down p75NTR is neuroprotective in vivo, we intercrossed gp120 transgenic (tg) mice with p75NTR heterozygous mice to obtain gp120tg mice lacking one or two p75NTR alleles. The removal of p75NTR alleles inhibited gp120-mediated decrease of excitatory synapses in the hippocampus, as measured by the levels of PSD95 and subunits of the N-methyl-D-Aspartate receptor in synaptosomes. Moreover, the deletion of only one copy of the p75NTR gene was sufficient to restore the cognitive impairment observed in gp120tg mice. Our data suggest that activation of p75NTR is one of the mechanisms crucial for the neurotoxic effect of gp120. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by HIV.

Highlights

Despite the use of combination antiretroviral therapy (Ellis et al, 2007; Everall et al, 2009), approximately half of human immunodeficiency virus-1 (HIV)-positive individuals are at a high risk for developing mild to severe cognitive impairments, termed HIV-associated neurocognitive disorders (HANDs) (Clifford and Ances, 2013; Saylor et al, 2016)
Note that the neuronal network (TUBB3 positive processes) in p75 neurotrophin receptor (p75NTR)–/– neurons exposed to gp120 is preserved when compared to Wild type (WT) neurons exposed to gp120
We have previously shown that gp120 causes a decrease in the number of dendritic spines in the hippocampus, an effect that is significantly diminished by the removal of one p75NTR allele (Bachis et al, 2016b)

Summary

Introduction

Despite the use of combination antiretroviral therapy (cART) (Ellis et al, 2007; Everall et al, 2009), approximately half of HIV-positive individuals are at a high risk for developing mild to severe cognitive impairments, termed HIV-associated neurocognitive disorders (HANDs) (Clifford and Ances, 2013; Saylor et al, 2016). A better understanding of the molecular mechanisms underlying HIV neurotoxicity could lead to a new adjunct therapy for HIV positive individuals. HIV does not infect neurons and HAND must result from mechanisms other than neuronal infection. The loss of neurons, simplification of neuronal branching, and reduction in dendritic spines can be triggered by the p75 neurotrophin receptor (p75NTR) (reviewed in Ibanez and Simi, 2012), a member of the tumor necrosis factor receptor family which contains a death domain (Feinstein et al, 1995; Liepinsh et al, 1997). Activation of p75NTR induces neuronal cell death (Teng et al, 2005) as well as axonal and dendritic spine pruning both during development (Singh et al, 2008) as well as in the adult nervous system (Park et al, 2010; Kraemer et al, 2014)

Methods

Results

Conclusion