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

Valentina Latina, Silvia Caioli, Cristina Zona, Maria Teresa Ciotti, Antonella Borreca, Pietro Calissano, Giuseppina Amadoro

Research output: Contribution to journalArticle

Abstract

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 α-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 (-1 h up to -6 h); (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 -6 h 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 nerve terminals from hippocampi of transgenic Tg2576 AD mice, even from presymptomatic stages of neuropathology (1-month-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.

Original languageEnglish
Article number487
JournalFrontiers in Cellular Neuroscience
Volume12
DOIs
Publication statusPublished - Dec 13 2018

Fingerprint

Animal Disease Models
Nerve Growth Factor
Ubiquitin
Cholinergic Agents
Alzheimer Disease
Homeostasis
Proteasome Endopeptidase Complex
Ubiquitin Thiolesterase
Cholinergic Neurons
Synucleins
Synapsins
Prodromal Symptoms
Neurons
Ubiquitination
Nerve Growth Factors
Protein Transport
Starvation
Synaptic Transmission
Synapses
Proteolysis

Keywords

  • Alzheimer’s disease
  • Cholinergic synapse(s)
  • Nerve growth factor
  • Neurodegeneration
  • Ubiquitin-C-terminal hydrolase 1
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

NGF-dependent changes in ubiquitin homeostasis trigger early cholinergic degeneration in cellular and animal AD-model. / Latina, Valentina; Caioli, Silvia; Zona, Cristina; Ciotti, Maria Teresa; Borreca, Antonella; Calissano, Pietro; Amadoro, Giuseppina.

In: Frontiers in Cellular Neuroscience, Vol. 12, 487, 13.12.2018.

Research output: Contribution to journalArticle

Latina, Valentina ; Caioli, Silvia ; Zona, Cristina ; Ciotti, Maria Teresa ; Borreca, Antonella ; Calissano, Pietro ; Amadoro, Giuseppina. / NGF-dependent changes in ubiquitin homeostasis trigger early cholinergic degeneration in cellular and animal AD-model. In: Frontiers in Cellular Neuroscience. 2018 ; Vol. 12.
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