Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP

Kamal, Adeela; Almenar-Queralt, Angels; LeBlanc, James F.; Roberts, Elizabeth A.; Goldstein, Lawrence S.B.

doi:10.1038/414643a

Cited by 528 publications

(469 citation statements)

References 30 publications

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“…Nonetheless, numerous factors implicated in AD including oxidative stress (de la Monte et al, 2000;Perry and Smith, 1997;Smith et al, 1995), APO e (Tesseur et al, 2000), and APP-L (Torroja et al, 1999) have all been shown to affect axonal transport. The observation that AbPP can serve as a kinesin cargo receptor (Kamal et al, 2000(Kamal et al, , 2001 as well as the inhibition of kinesin-dependent transport by tau overexpression (Ebneth et al, 1998;Stamer et al, 2002) should not be overlooked. It would be interesting to see whether tau overexpression and Al affect intracellular transport via a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

et al. 2004

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Aluminum (Al) compounds are neurotoxic and have been shown to induce experimental neurodegeneration although the mechanism of this effect is unclear. In order to study this neurotoxic effect of Al, we have developed an in vitro model system using Al maltolate and human NT2 cells. Al maltolate at 500 mM caused significant cell death with a 24-h incubation and this toxicity was even more evident after 48 h. Lower doses of Al maltolate were also effective, but required a longer incubation for cell death. Nuclear fragmentation suggestive of apoptosis was observed as early as three hours and increased substantially through 24 h. Chromatin condensation and nuclear fragmentation were confirmed by electron microscopy. In addition, TUNEL positive nuclei were also observed. The release of cytochrome c was demonstrated with Western blot analysis. This in vitro model using human cells adds to our understanding of Al neurotoxicity and could provide insight into the neurodegenerative processes in human disease. #

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Section: Discussionmentioning

confidence: 99%

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

et al. 2004

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“…A detailed analysis aimed at determining the ratio of axonally versus dendritically secreted Ab, using for example cultured neurons in compartmentalized chambers, has not been performed. It has been suggested that APP is transported in axonal vesicles which harbor b-and g-secretase and that consequently Ab is produced in these vesicles (Kamal et al 2001). This view has been challenged, and several experiments indicate that APP is not processed in axonal transport vesicles, with the exception of limited processing by a-secretase.…”

Section: Subcellular Sites Of G-secretase-mediated App Processingmentioning

confidence: 94%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

871

890

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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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“…The binding interaction was mapped to amino acids 867-894 of US11 and the heptad repeat cargobinding domain of kinesin. Satpute-Krishnan et al also showed that amyloid precursor protein, a putative kinesin receptor, 121,122 associates with viral particles during anterograde transport. Similar to retrograde movement, data are accumulating that HSV nucleocapsids and tegument travel separately from envelope components in anterograde transport.…”

Section: Virus Attachment and Entrymentioning

confidence: 98%

HSV trafficking and development of gene therapy vectors with applications in the nervous system

et al. 2005

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Herpes simplex virus type 1 (HSV-1) is a neurotropic doublestranded DNA virus that causes cold sores, keratitis, and rarely encephalitis in humans. Nonpathogenic HSV-1 gene transfer vectors have been generated by elimination of viral functions necessary for replication. The life cycle of the native virus includes replication in epithelial cells at the site of initial inoculation followed by retrograde axonal transport to the nuclei of sensory neurons innervating the area of cutaneous primary infection. In this review, we summarize the current understanding of the molecular basis for HSV cell entry, nuclear transport of the genome, virion egress following replication, and retrograde and anterograde axonal transport in neurons. We discuss how each of these properties has been exploited or modified to allow the generation of gene transfer vectors with particular utility for neurological applications. Recent advances in engineering virus entry have provided proof of principle that vector targeting is possible. Furthermore, significant and potentially therapeutic modifications to the pathological responses to various noxious insults have been demonstrated in models of peripheral nerve disease. These applications exploit the natural axonal transport mechanism of HSV, allowing transgene expression in the cell nucleus within the inaccessible trigeminal ganglion or dorsal root ganglion, following the noninvasive procedure of subcutaneous vector inoculation. These findings demonstrate the importance of understanding basic virology in the design of vector systems and the powerful approach of exploiting favorable properties of the parent virus in the generation of gene transfer vectors. Gene Therapy (2005) 12, 891-901.

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Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP

Cited by 528 publications

References 30 publications

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

Trafficking and Proteolytic Processing of APP

HSV trafficking and development of gene therapy vectors with applications in the nervous system

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