The internalization and retrograde axonal transport of neurotrophin receptors is important for their retrograde signal transduction supporting neuronal differentiation, plasticity, and survival. To influence transcription, neurotrophin signals initiated at synapses have to be conveyed retrogradely to the cell body. Signaling endosomes containing neurotrophin receptor signaling complexes mediate retrograde neurotrophin signaling from synapses to the nucleus. Interestingly, many neurodegenerative diseases, including Alzheimer's disease, Niemann Pick disease Type C, and Charcot-Marie-Tooth neuropathies, show alterations of vesicular transport, suggesting that traffic jams within neuronal processes may cause neurodegeneration. Although most of these diseases are complex and may be modulated by diverse pathways contributing to neuronal death, altered neurotrophin transport is emerging as a strong candidate influence on neurodegeneration. In this article, we review the mechanisms of internalization and endocytic trafficking of neurotrophin receptors, and discuss the potential roles of perturbations in neurotrophin trafficking in a number of neurodegenerative diseases.

Neurotrophins are trophic factors that regulate important neuronal functions. They bind two unrelated receptors, the Trk family of receptor-tyrosine kinases and the p75 neurotrophin receptor (p75). p75 was recently identified as a new substrate for ␥-secretase-mediated intramembrane proteolysis, generating a p75-derived intracellular domain (p75-ICD) with signaling capabilities. Using PC12 cells as a model, we studied how neurotrophins activate p75 processing and where these events occur in the cell. We demonstrate that activation of the TrkA receptor upon binding of nerve growth factor (NGF) regulates the metalloprotease-mediated shedding of p75 leaving a membranebound p75 C-terminal fragment (p75-CTF). Using subcellular fractionation to isolate a highly purified endosomal fraction, we demonstrate that p75-CTF ends up in endosomes where ␥-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for ␥-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75.Neurotrophins belong to a small family of neurotrophic factors that include nerve growth factor (NGF), 4 brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4). They regulate different aspects of the developing and adult nervous system by binding to specific members of the Trk family of receptor-tyrosine kinases (TrkA, -B, and -C) or to the p75 neurotrophin receptor (p75). Their involvement includes neuronal migration, cell death, axonal elongation, myelinization, neuronal differentiation, and synaptic plasticity (1-3). p75 is a multifunctional type I transmembrane protein that is structurally related to the tumor necrosis factor receptor superfamily. It binds all neurotrophins, alone or in complex with Trk receptors, but also other ligands such as amyloid peptides and pro-neurotrophins (4, 5). The association of p75 with different receptors shapes the outcome of a signaling event. For example, binding of p75 to TrkA in the presence of NGF promotes neuronal survival, whereas interaction with the Nogo receptor (NgR) in the presence of its ligands, such as Nogo and myelin-associated glycoprotein (MAG), results in growth cone collapse and the inhibition of axonal regeneration (1, 4, 5). In addition, different downstream p75-associated signaling cascades are triggered through the interaction of its cytosolic portion with multiple adaptor proteins (6). Neurotrophin binding to p75 also induces accumulation of p75 in recycling endosomes where it associates with specific p75 downstream signaling effectors (7-9). Hence trafficking of p75 in the cell body or in axons (10, 11) may determine downstream signaling of p75 as previously shown for Trk receptors (12). The regulation of p75 signaling becomes even more complicated with the finding that p75 is subject to a dual processing starting with shedding of the ectodomain and followed by ␥-secretase cleavage. Thi...

The p75 neurotrophin receptor (p75, also known as NGFR) is a multifaceted signalling receptor that regulates neuronal physiology, including neurite outgrowth, and survival and death decisions. A key cellular aspect regulating neurotrophin signalling is the intracellular trafficking of their receptors; however, the post-endocytic trafficking of p75 is poorly defined. We used sympathetic neurons and rat PC12 cells to study the mechanism of internalisation and postendocytic trafficking of p75. We found that p75 internalisation depended on the clathrin adaptor protein AP2 and on dynamin. More surprisingly, p75 evaded the lysosomal route at the level of the early endosome, instead accumulating in two different types of endosomes, Rab11-positive endosomes and multivesicular bodies (MVBs) positive for CD63, a marker of the exosomal pathway. Consistently, depolarisation by KCl induced the liberation of previously endocytosed full-length p75 into the extracellular medium in exosomes. Thus, p75 defines a subpopulation of MVBs that does not mature to lysosomes and is available for exosomal release by neuronal cells.

Background: The generation of the amyloid-β peptide (Aβ) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing.

Neurons possess a polarized morphology specialized to contribute to neuronal networks, and this morphology imposes an important challenge for neuronal signaling and communication. The physiology of the network is regulated by neurotrophic factors that are secreted in an activity-dependent manner modulating neuronal connectivity. Neurotrophins are a well-known family of neurotrophic factors that, together with their cognate receptors, the Trks and the p75 neurotrophin receptor, regulate neuronal plasticity and survival and determine the neuronal phenotype in healthy and regenerating neurons. Is it now becoming clear that neurotrophin signaling and vesicular transport are coordinated to modify neuronal function because disturbances of vesicular transport mechanisms lead to disturbed neurotrophin signaling and to diseases of the nervous system. This chapter summarizes our current understanding of how the regulated secretion of neurotrophin, the distribution of neurotrophin receptors in different locations of neurons, and the intracellular transport of neurotrophin-induced signaling in distal processes are achieved to allow coordinated neurotrophin signaling in the cell body and axons.