Axonal Membrane Proteins Are Transported in Distinct Carriers: A Two-Color Video Microscopy Study in Cultured Hippocampal Neurons

Kaether, Christoph; Skehel, Paul; Dotti, Carlos G.

doi:10.1091/mbc.11.4.1213

Cited by 255 publications

(280 citation statements)

References 44 publications

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“…APP delivery to the axon makes use of the fast axonal transport system Sisodia et al 1993), with kinesin-1 as the microtubule motor protein (reviewed in Kins et al 2006). As visualized by GFP-tagged fusion proteins, APP is transported in vesicular and often elongated tubular structures which move with special characteristics along the axon (Kaether et al 2000;Stamer et al 2002;Goldsbury et al 2006;Szodorai et al 2009). Whereas most other proteins are axonally transported in vesicles that display a saltatory movement, often changing directions, the APP tubules continuously move unidirectionally, with an average speed of 4.5 mm/s, reaching maximal speeds up to 10 mm/s (Kaether et al 2000).…”

Section: Trafficking Of App In Neuronsmentioning

confidence: 99%

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Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Section: Trafficking Of App In Neuronsmentioning

confidence: 99%

“…This is among the fastest transport velocities measured in cultured neurons. Significant retrograde transport with slightly slower kinetics was also observed (Kaether et al 2000;Stamer et al 2002). Little is known about the fate of the axonal transport carrier vesicles.…”

Section: Trafficking Of App In Neuronsmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

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“…It has been previously established that APP exits the TGN in polarized and nonpolarized cells by using the basolateral sorting machinery (Haass et al, 1994;Simons et al, 1995;Tienari et al, 1996a,b;Kaether et al, 2000), so it can be found on post-Golgi carriers costaining with markers of this pathway, including VSVG protein. Results in our laboratory using HeLa, Chinese hamster ovary, or primary cultured mouse hippocampal neuronal cells have confirmed these findings (data not shown).…”

Section: Knockdown Of Mint3 Alters App Trafficmentioning

confidence: 99%

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Shrivastava-Ranjan

Faúndez

Fang

et al. 2008

MBoC

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␤-Amyloid peptides (A␤) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the ␤-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic ␤-amyloid peptide, A␤ 1-40 . Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic. INTRODUCTIONThe hallmark of Alzheimer's disease is the presence in brain of plaques that contain A␤ peptides, formed by the result of proteolytic processing of the ␤-amyloid precursor protein (APP). APP is a ubiquitous, single-pass transmembrane protein of unknown function that is highly expressed in brain. Processing involves the sequential actions of ␣-or ␤-plus ␥-secretases, each of which are found in multiple cellular locations (Kuentzel et al., 1993;Selkoe, 1998;Yan et al., 2001). Although processing may occur at any step, the trans-Golgi network (TGN) is the earliest site at which APP processing is thought to commence, and APP is internalized from the cell surface to endosomal compartments where ␥-secretase also acts (Selkoe et al., 1996;Greenfield et al., 1999;Lah and Levey, 2000;Bagshaw et al., 2003).The C-terminal domain of APP contains the tyrosinebased sorting motif, YENPTY, which is conserved across species and a determinant of APP traffic (Perez et al., 1999;Bonifacino and Traub, 2003;King et al., 2004). Such sorting motifs function by binding specific adaptors to facilitate their selective import into budding carriers and ensure specificity in cargo selection and coat recruitment. The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al., 1996(Borg et al., , 1998Zhang et al., 1997;Sastre et al., 1998;Tanahashi and Tabira, 1999;Tomita et al., 1999;Ho et al., 2002;Araki et al., 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al., 1999) family, Dab2 (Howell et al., 1999), JIP1b (King et al....

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“…To label presynaptic synapses (output synapses), we used a synaptophysin:GFP fusion protein. Synaptophysin:GFP was the first synaptic vesicle protein to be cloned and has been extensively used to study the distribution and density of presynaptic sites in neurons both in vitro and in vivo (17)(18)(19)(20)(21)(22).We labeled progenitors for GC neurons with these genetic markers to visualize their synapse development, and observed that in adult-generated neurons, PSD-95:GFP-positive clusters (PSD ϩ C) developed initially at high density in the proximal 15% of the unbranched apical dendrite. We therefore defined the proximal 15% of the unbranched apical dendrite as the proximal domain.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Sequential development of synapses in dendritic domains during adult neurogenesis

Kelsch

Lin²,

Lois³

2008

Proc. Natl. Acad. Sci. U.S.A.

126

178

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During the process of integration into brain circuits, new neurons develop both input and output synapses with their appropriate targets. The vast majority of neurons in the mammalian brain are generated before birth and integrate into immature circuits while these are being assembled. In contrast, adult-generated neurons face an additional challenge as they integrate into a mature, fully functional circuit. Here, we examined how synapses of a single neuronal type, the granule cell in the olfactory bulb, develop during their integration into the immature circuit of the newborn and the fully mature circuit of the adult rat. We used a genetic method to label pre and postsynaptic sites in granule neurons and observed a stereotypical development of synapses in specific dendritic domains. In adult-generated neurons, synapses appeared sequentially in different dendritic domains with glutamatergic input synapses that developed first at the proximal dendritic domain, followed several days later by the development of inputoutput synapses in the distal domain and additional input synapses in the basal domain. In contrast, for neurons generated in neonatal animals, input and input-output synapses appeared simultaneously in the proximal and distal domains, respectively, followed by the later appearance of input synapses to the basal domain. The sequential formation of synapses in adult-born neurons, with input synapses appearing before output synapses, may represent a cellular mechanism to minimize the disruption caused by the integration of new neurons into a mature circuit in the adult brain.bulb ͉ dendrite I ntegration of new neurons continues throughout life in the adult mammalian olfactory bulb (OB) (1, 2). During the process of integration into brain circuits, new neurons develop both input and output synapses with their appropriate targets. Whereas the majority of neurons in the olfactory bulb integrate into an immature circuit while it is being assembled, neurons generated in adulthood face an additional challenge as they integrate into a mature, fully functional circuit. In particular, the formation of synapses by a new neuron in a functioning circuit may interfere with circuit operation and, thus, it could result in maladaptive behaviors. Additionally, it is still not known whether new neurons integrating into the neonatal and adult olfactory system have the same or different functions in the circuit and, therefore, adult-and neonatal-generated neurons could employ different modes of integration. To compare how new neurons are added to neonatal and adult circuits, we examined the pattern of synapse development of a single neuronal type, the granule cell (GC) in the olfactory bulb, during its integration into the immature circuit of the newborn and the mature circuit of the adult rat.The majority of neurons added to the OB of adult rats are GC neurons. GCs are axonless inhibitory interneurons that have both a basal dendrite and an apical dendrite (Fig. 1A). The apical dendrite can be divided into an unbranched segm...

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Axonal Membrane Proteins Are Transported in Distinct Carriers: A Two-Color Video Microscopy Study in Cultured Hippocampal Neurons

Cited by 255 publications

References 44 publications

Trafficking and Proteolytic Processing of APP

Trafficking and Proteolytic Processing of APP

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Sequential development of synapses in dendritic domains during adult neurogenesis

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