Membrane traffic in polarized neurons

AbstractThe plasma membrane of neurons can be divided into two domains, the soma-dendritic and the axonal. These domains perform different functions: the dendritic surface receives and processes information while the axonal surface is specialized for the rapid transmission of electrical impulses. This functional specialization is generated by sorting and anchoring mechanisms that guarantee the correct delivery and retention of specific membrane proteins. Our understanding of neuronal membrane protein sorting is primarily based on studies of protein overexpression in cultured neurons. These studies revealed that newly synthesized membrane proteins are segregated in the Golgi apparatus in the cell body from where they are transported to the axonal or dendritic surface. Such segregation presumably depends on sorting motifs in the proteins’ primary structure. They appear to be located in the cytoplasmic tail for dendritic proteins and in the transmembrane-ectodomain for axonal proteins. Recent studies on neurotransmitter segregation suggest that anchoring in the correct subdomain of the plasma membrane also requires cytoplasmic tail information for binding to the cytoskeleton either directly or by linker proteins. Both mechanisms, sorting and retention, gradually mature during neural development. Young neurons appear to develop initial polarity by other mechanisms, presumably analogous to the mechanisms used by migrating cells

Amyloid excess in Alzheimer’s disease: What is cholesterol to be blamed for?

AbstractA link between alterations in cholesterol homeostasis and Alzheimer’s disease (AD) is nowadays widely accepted. However, the molecular mechanism/s underlying such link remain unclear. Numerous experimental evidences support the view that changes in neuronal membrane cholesterol levels and/or subcellular distribution determine the aberrant accumulation of the amyloid peptide in the disease. Still, this view comes from rather contradictory data supporting the existence of either high or low brain cholesterol content. This is of particular concern considering that therapeutical strategies aimed to reduce cholesterol levels are already being tested in humans. Here, we review the molecular mechanisms proposed and discuss the perspectives they open

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

© 2015 Elsevier Inc. The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes. Pasciuto etal. show that dual dysregulation of APP and ADAM10, during a critical period of postnatal development, leads to overproduction of sAPPα. Modulation of ADAM10 activity re-establishes physiological sAPPα levels and ultimately ameliorates FXS molecular, synaptic, and behavioral deficits.Stichting Alzheimer Onderzoek -Fondation Recherche Maladie Alzheimer (SAO-FMA), Vlaams Instituut voor Biotechnologie (VIB), KU Leuven (Opening the Future), European Research Projects on Neurodevelopmental Disorders NEURON ERA-NET, Associazione Italiana Sindrome X Fragile, Compagnia San Paolo, and Fondation Jerome Lejeune to C.B., a European Research Council Grant ERC-2010-AG_268675 to B.D.S.; a Methusalem grant of the KU Leuven/Flemish Government to B.D.S. and C.D. B.D.S. is supported by the Bax-Vanluffelen Chair for Alzheimer’s Disease. C.B. and B.D.S. are supported by ‘‘Opening the Future’’ of the Leuven Universiteit Fonds (LUF). Deutsche Forschungsgemeinschaft (DFG) (MU 1457/8-1; 1457/9-1)Peer Reviewe

Cadherins as regulators of neuronal polarity

A compelling amount of data is accumulating about the polyphonic role of neuronal cadherins during brain development throughout all developmental stages, starting from the involvement of cadherins in the organization of neurulation up to synapse development and plasticity. Recent work has confirmed that specifically N-cadherins play an important role in asymmetrical cellular processes in developing neurons that are at the basis of polarity. In this review we will summarize recent data, which demonstrate how N-cadherin orchestrates distinct processes of polarity establishment in neurons.Peer Reviewe

Plasmin Deficiency in Alzheimer's Disease Brains: Causal or Casual?

Substantial recent evidence suggests that defects in amyloid peptide degradation can be at the base of cases of sporadic Alzheimer's disease (AD). Among the discovered brain enzymes with the capacity to degrade amyloid peptide, the serine protease plasmin acquires special physiological relevance because of its low levels in areas of AD human brains with a high susceptibility to amyloid plaque accumulation. In this article we comment on a series of observations supporting the fact that plasmin paucity in the brain is not simply a secondary event in the disease but rather a primary defect in certain cases of sporadic AD. We also refer to recent data pointing to alterations in raft membrane domains and diminished membrane cholesterol as the underlying cause. Finally, we discuss the possibility that plasmin deficiency in the brain could lead to AD symptomatology because of amyloid aggregation and the triggering of cell death signaling cascades

The collagen chaperone HSP47 is a new interactor of APP that affects the levels of extracellular beta-amyloid peptides.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Ab peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Ab peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.The first is project n. A134, funded under the call ‘‘Bando Regionale sulla Ricerca Scientifica Applicata – 2004’’. The second is the DRUIDI (DRUg development In DIsease) project, funded under the call ‘‘Piattaforme Tecnologiche Innovative – 2008’’. The funder (Piedmont Region) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer Reviewe

Neuronal (Bi)Polarity as a Self-Organized Process Enhanced by Growing Membrane

Early in vitro and recent in vivo studies demonstrated that neuronal polarization occurs by the sequential formation of two oppositely located neurites. This early bipolar phenotype is of crucial relevance in brain organization, determining neuronal migration and brain layering. It is currently considered that the place of formation of the first neurite is dictated by extrinsic cues, through the induction of localized changes in membrane and cytoskeleton dynamics leading to deformation of the cells' curvature followed by the growth of a cylindrical extension (neurite). It is unknown if the appearance of the second neurite at the opposite pole, thus the formation of a bipolar cell axis and capacity to undergo migration, is defined by the growth at the first place, therefore intrinsic, or requires external determinants. We addressed this question by using a mathematical model based on the induction of dynamic changes in one pole of a round cell. The model anticipates that a second area of growth can spontaneously form at the opposite pole. Hence, through mathematical modeling we prove that neuronal bipolar axis of growth can be due to an intrinsic mechanism

Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor–dependent manner

Actin is the major cytoskeletal source of dendritic spines, which are highly specialized protuberances on the neuronal surface where excitatory synaptic transmission occurs (Harris, K.M., and S.B. Kater. 1994. Annu. Rev. Neurosci. 17:341–371; Yuste, R., and D.W. Tank. 1996. Neuron. 16:701–716). Stimulation of excitatory synapses induces changes in spine shape via localized rearrangements of the actin cytoskeleton (Matus, A. 2000. Science. 290:754–758; Nagerl, U.V., N. Eberhorn, S.B. Cambridge, and T. Bonhoeffer. 2004. Neuron. 44:759–767). However, what remains elusive are the precise molecular mechanisms by which different neurotransmitter receptors forward information to the underlying actin cytoskeleton. We show that in cultured hippocampal neurons as well as in whole brain synaptosomal fractions, RhoA associates with glutamate receptors (GluRs) at the spine plasma membrane. Activation of ionotropic GluRs leads to the detachment of RhoA from these receptors and its recruitment to metabotropic GluRs. Concomitantly, this triggers a local reduction of RhoA activity, which, in turn, inactivates downstream kinase RhoA-specific kinase, resulting in restricted actin instability and dendritic spine collapse. These data provide a direct mechanistic link between neurotransmitter receptor activity and the changes in spine shape that are thought to play a crucial role in synaptic strength

N-cadherin: A new player in neuronal polarity

Comment on: Gärtner A, et al. EMBO J 2012; <span class="b">31</span>:1893-90