QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 27, 2007, 27(26):7011-7020; doi:10.1523/JNEUROSCI.4272-06.2007

This Article Full Text Full Text (PDF) A correction has been published Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Lazarov, O. Articles by Sisodia, S. S. Search for Related Content PubMed PubMed Citation Articles by Lazarov, O. Articles by Sisodia, S. S.

 Previous Article  |  Next Article 

Neurobiology of Disease
Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Orly Lazarov,^1 * Gerardo A. Morfini,^1 * Gustavo Pigino,¹ Archana Gadadhar,¹ Xiangjun Chen,² John Robinson,³ Hanson Ho,² Scott T. Brady,¹ and Sangram S. Sisodia³

¹Department of Anatomy and Cell Biology, The University of Illinois at Chicago, Chicago, Illinois 60612, and ²Departments of Neurology and ³Neurobiology, The University of Chicago, Chicago, Illinois 60637

Correspondence should be addressed to Sangram S. Sisodia, Department of Neurobiology, The University of Chicago, 947 E. 58th Street, MC0926, Chicago, IL 60637. Email: ssisodia{at}bsd.uchicago.edu

Presenilins (PS) play a central role in -secretase-mediated processing of ß-amyloid precursor protein (APP) and numerous type I transmembrane proteins. Expression of mutant PS1 variants causes familial forms of Alzheimer's disease (FAD). In cultured mammalian cells that express FAD-linked PS1 variants, the intracellular trafficking of several type 1 membrane proteins is altered. We now report that the anterograde fast axonal transport (FAT) of APP and Trk receptors is impaired in the sciatic nerves of transgenic mice expressing two independent FAD-linked PS1 variants. Furthermore, FAD-linked PS1 mice exhibit a significant increase in phosphorylation of the cytoskeletal proteins tau and neurofilaments in the spinal cord. Reductions in FAT and phosphorylation abnormalities correlated with motor neuron functional deficits. Together, our data suggests that defects in anterograde FAT may underlie FAD-linked PS1-mediated neurodegeneration through a mechanism involving impairments in neurotrophin signaling and synaptic dysfunction.

Key words: Alzheimer's disease; presenilin; kinesin; protein trafficking; axonal transport; motor neurons; tau; neurofilament; kinase; GSK-3

---

Received Sept. 30, 2006; revised May 20, 2007; accepted May 20, 2007.

Correspondence should be addressed to Sangram S. Sisodia, Department of Neurobiology, The University of Chicago, 947 E. 58th Street, MC0926, Chicago, IL 60637. Email: ssisodia{at}bsd.uchicago.edu

This article has been cited by other articles:

				G. A. Morfini, M. Burns, L. I. Binder, N. M. Kanaan, N. LaPointe, D. A. Bosco, R. H. Brown Jr, H. Brown, A. Tiwari, L. Hayward, et al. Axonal Transport Defects in Neurodegenerative Diseases J. Neurosci., October 14, 2009; 29(41): 12776 - 12786. [Abstract] [Full Text] [PDF]

				A. Lim and R. Kraut The Drosophila BEACH Family Protein, Blue Cheese, Links Lysosomal Axon Transport with Motor Neuron Degeneration J. Neurosci., January 28, 2009; 29(4): 951 - 963. [Abstract] [Full Text] [PDF]

				Q. Chen, C. A. Peto, G. D. Shelton, A. Mizisin, P. E. Sawchenko, and D. Schubert Loss of Modifier of Cell Adhesion Reveals a Pathway Leading to Axonal Degeneration J. Neurosci., January 7, 2009; 29(1): 118 - 130. [Abstract] [Full Text] [PDF]

				G. B. Stokin, A. Almenar-Queralt, S. Gunawardena, E. M. Rodrigues, T. Falzone, J. Kim, C. Lillo, S. L. Mount, E. A. Roberts, E. McGowan, et al. Amyloid precursor protein-induced axonopathies are independent of amyloid-{beta} peptides Hum. Mol. Genet., November 15, 2008; 17(22): 3474 - 3486. [Abstract] [Full Text] [PDF]

				I. Cuchillo-Ibanez, A. Seereeram, H. L. Byers, K.-Y. Leung, M. A. Ward, B. H. Anderton, and D. P. Hanger Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin FASEB J, September 1, 2008; 22(9): 3186 - 3195. [Abstract] [Full Text] [PDF]

				P. Thomas and M. Fenech Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease Mutagenesis, January 1, 2008; 23(1): 57 - 65. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help