European Brain Research Institute Rome

Rome, Italy

European Brain Research Institute Rome

Rome, Italy
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Canu N.,University of Rome Tor Vergata | Canu N.,National Research Council Italy | Amadoro G.,National Research Council Italy | Triaca V.,National Research Council Italy | And 6 more authors.
International Journal of Molecular Sciences | Year: 2017

Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology. This is mainly based on the finding that TrkA receptor binding to APP depends on a minimal stretch of ~20 amino acids located in the juxtamembrane/extracellular domain of APP that carries the α-and β-secretase cleavage sites. Here, we provide evidence that: (i) NGF could be one of the “routing” proteins responsible for modulating the metabolism of APP from amyloidogenic towards non-amyloidogenic processing via binding to the TrkA receptor, (ii) the loss of NGF/TrkA signaling could be linked to sporadic AD contributing to the classical hallmarks of the neuropathology, such as synaptic loss, β-amyloid peptide (Aβ) deposition and tau abnormalities. These findings will hopefully help to design therapeutic strategies for AD treatment aimed at preserving cholinergic function and anti-amyloidogenic activity of the physiological NGF/TrkA pathway in the septo-hippocampal system. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.

Bornstein S.R.,TU Dresden | Ehrhart-Bornstein M.,TU Dresden | Androutsellis-Theotokis A.,TU Dresden | Androutsellis-Theotokis A.,European Brain Research Institute Rome | And 9 more authors.
Molecular Psychiatry | Year: 2012

Chromaffin cells probably are the most intensively studied of the neural crest derivates. They are closely related to the nervous system, share with neurons some fundamental mechanisms and thus were the ideal model to study the basic mechanisms of neurobiology for many years. The lessons we have learned from chromaffin cell biology as a peripheral model for the brain and brain diseases pertain more than ever to the cutting edge research in neurobiology. Here, we highlight how studying this cell model can help unravel the basic mechanisms of cell renewal and regeneration both in the central nervous system (CNS) and neuroendocrine tissue and also can help in designing new strategies for regenerative therapies of the CNS. © 2012 Macmillan Publishers Limited All rights reserved.

PubMed | European Brain Research Institute Rome
Type: | Journal: Frontiers in computational neuroscience | Year: 2013

The role of amyloid beta (A) in brain function and in the pathogenesis of Alzheimers disease (AD) remains elusive. Recent publications reported that an increase in A concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that A is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this A-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz). Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced A on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-A condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased A can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during AD.

PubMed | European Brain Research Institute Rome, Stanford University and Ecole Normale Superieure de Paris
Type: | Journal: Frontiers in neuroscience | Year: 2014

Hypothalamic orexin/hypocretin neurons send long axonal projections through the dorsal spinal cord in lamina I-II of the dorsal horn (DH) at the interface with the peripheral nervous system (PNS). We show that in the DH OXA fibers colocalize with substance P (SP) positive afferents of dorsal root ganglia (DRG) neurons known to mediate sensory processing. Further, OR1 is expressed in p75(NTR) and SP positive DRG neurons, suggesting a potential signaling pathway between orexin and DRG neurons. Interestingly, DRG sensory neurons have a distinctive bifurcating axon where one branch innervates the periphery and the other one the spinal cord (pseudo-unipolar neurons), allowing for potential functional coupling of distinct targets. We observe that OR1 is transported selectively from DRG toward the spinal cord, while OXA is accumulated retrogradely toward the DRG. We hence report a rare situation of asymmetrical neuropeptide receptor distribution between axons projected by a single neuron. These molecular and cellular data are consistent with the role of OXA/OR1 in sensory processing, including DRG neuronal modulation, and support the potential existence of an OX/HCRT circuit between CNS and PNS.

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