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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00487

NGF-dependent changes in ubiquitin homeostasis trigger early cholinergic degeneration in cellular and animal AD-model.

 Giuseppina Amadoro1, 2*,  Valentina Latina2, Silvia Caioli3,  Cristina Zona3, 4, Maria Teresa Ciotti2,  Antonella Borreca5 and  Pietro Calissano2
  • 1Istituto di Farmacologia Traslazionale (IFT), Italy
  • 2European Brain Research Institute, Italy
  • 3Fondazione Santa Lucia (IRCCS), Italy
  • 4Università degli Studi di Roma Tor Vergata, Italy
  • 5Institute of Cell Biology and Neurobiology, CNR, Italy

Basal Forebrain Cholinergic Neurons (BFCNs) depend on Nerve Growth Factor (NGF) for their survival/differentiation and innervate cortical and hippocampal regions involved in memory/learning processes. Cholinergic hypofunction and/or degeneration early occurs at prodromal stages of Alzheimer’s Disease (AD) neuropathology in correlation with synaptic damages, cognitive decline and behavioral disability. Alteration(s) in ubiquitin-proteasome system (UPS) is also a pivotal AD hallmark but whether it plays a causative, or only a secondary role, in early synaptic failure associated with disease onset remains unclear. We previously reported that impairment of NGF/TrkA signaling pathway in cholinergic-enriched septo-hippocampal primary neurons triggers “dying-back” degenerative processes which occur prior to cell death in concomitance with loss of specific vesicle trafficking proteins, including synapsin I, SNAP-25 and a-synuclein, and with deficit in presynaptic excitatory neurotransmission. Here, we show that in this in vitro neuronal model:(i) UPS stimulation early occurs following neurotrophin starvation (-1h up to -6h); (ii) NGF controls the steady-state levels of these three presynaptic proteins by acting on coordinate mechanism(s) of dynamic Ubiquitin-C-terminal Hydrolase 1 (UCHL-1)-dependent (mono)ubiquitin turnover and UPS–mediated protein degradation. Importantly, changes in miniature Excitatory Post-Synaptic Currents (mEPSCs) frequency detected in -6h NGF-deprived primary neurons are strongly reverted by acute inhibition of UPS and UCHL-1, indicating that NGF tightly controls in vitro the presynaptic efficacy via ubiquitination-mediated pathway(s). Finally, changes in synaptic ubiquitin and selective reduction of presynaptic markers are also found in vivo in cholinergic afferent nerve terminals from hippocampi of transgenic Tg2576 AD mice, even from presymptomatic stages of neuropathology (1-months-old). By demonstrating a crucial role of UPS in the dysregulation of NGF/TrkA signaling on properties of cholinergic synapses, these findings from two well-established cellular and animal AD models provide novel therapeutic targets to contrast early cognitive and synaptic dysfunction associated to selective degeneration of BFCNs occurring in incipient early/ middle-stage of disease.

Keywords: Alzheimer's disease, Nerve growth factor (NGF), cholinergic synapse(s), Ubiquitin-Proteasome-System (UPS), Ubiquitin-C-terminal Hydrolase 1 (UCHL-1), neurodegeneration

Received: 27 Sep 2018; Accepted: 29 Nov 2018.

Edited by:

Marco Martina, Northwestern University, United States

Reviewed by:

Hermona Soreq, Hebrew University of Jerusalem, Israel
Scott M. Wilson, University of Alabama at Birmingham, United States  

Copyright: © 2018 Amadoro, Latina, Caioli, Zona, Ciotti, Borreca and Calissano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Giuseppina Amadoro, Istituto di Farmacologia Traslazionale (IFT), Rome, 00133, Lazio, Italy,