NGF-Dependent Changes in Ubiquitin Homeostasis Trigger Early Cholinergic Degeneration in Cellular and Animal AD-Model

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.

A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

“…Cholinergic and dopaminergic neurotransmission is important for hippocampal-dependent synaptic plasticity and memory regulation [ 32 , 33 ]. For example, cholinergic hypofunction occurs at the prodromal stages of AD-associated cognitive decline [ 34 , 35 ]. Furthermore, the injection of a dopamine D1-receptor antagonist can block the novel object preference behavior in rodents [ 32 ].…”

Role of Cholinergic Signaling in Alzheimer’s Disease

“…Basic forebrain cholinergic neurons (BFCNs) have an important role in learning, memory, and cognitive function [ 12 ]. Their survival and differentiation depend on nerve growth factor (NGF) and dominate cortical and hippocampal areas involved in memory and learning processes [ 13 ]. The hippocampus is a brain region rich in nicotinic acetylcholine receptors (NACHR), particularly the α7 subtype [ 14 ].…”

“…In cellular and animal models of AD, NGF-dependent changes in ubiquitin-homeostasis trigger early cholinergic degradation. In an in vitro model of a septal hippocampal neuron rich in cholinergic energy, it is found that damage to the NGF/TrkA signaling pathway triggers a “death” degradation process that occurs before cell death, and NGF tightly controls excitatory neurotransmission in vitro through ubiquitination mediated pathways, accompanied by loss of specific vesicle transporters [ 13 ]. The endocannabinoid system regulates emotional learning and memory through the CB1 receptor and has been found to be unregulated in AD.…”

Synaptic tau: A pathological or physiological phenomenon?

“…The UPS is only responsible for the local degradation of a subset of synaptic proteins, and its function is regulated by synaptic activity or neural growth factors (NGF) to adjust the concentration of proteins important for synaptic function. This activitydependent or NGF-dependent UPS function can thereby feedback to regulate neurotransmitter release and synapse elimination [206,254,372,422].…”