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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 19, 2005, 25(42):9694-9703; doi:10.1523/JNEUROSCI.2980-05.2005

This Article Full Text Full Text (PDF) 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 (34) Citing Articles via Google Scholar Google Scholar Articles by Chin, J. Articles by Mucke, L. Search for Related Content PubMed PubMed Citation Articles by Chin, J. Articles by Mucke, L.

 Previous Article  |  Next Article 

Neurobiology of Disease
Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease

Jeannie Chin,^1,2 Jorge J. Palop,^1,2 Jukka Puoliväli,^1,2 Catherine Massaro,^1,3 Nga Bien-Ly,¹ Hilary Gerstein,¹ Kimberly Scearce-Levie,¹ Eliezer Masliah,⁴ and Lennart Mucke^1,2,3

¹Gladstone Institute of Neurological Disease, ²Department of Neurology, and ³Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California 94158, and ⁴Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, California 92093

Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid- (A) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates A-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of A production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher A levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of A. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate A levels, and inhibition of Fyn activity may help counteract A-induced impairments.

Key words: hippocampus; plasticity; amyloid ; Arc; spatial memory; striatal-enriched phosphatase (STEP)

---

Received July 19, 2005; revised August 30, 2005; accepted September 3, 2005.

This article has been cited by other articles:

				H.-C. Chiang, K. Iijima, I. Hakker, and Y. Zhong Distinctive roles of different {beta}-amyloid 42 aggregates in modulation of synaptic functions FASEB J, June 1, 2009; 23(6): 1969 - 1977. [Abstract] [Full Text] [PDF]

				J. J. Palop and L. Mucke Epilepsy and Cognitive Impairments in Alzheimer Disease Arch Neurol, April 1, 2009; 66(4): 435 - 440. [Abstract] [Full Text] [PDF]

				W. J. Meilandt, M. Cisse, K. Ho, T. Wu, L. A. Esposito, K. Scearce-Levie, I. H. Cheng, G.-Q. Yu, and L. Mucke Neprilysin Overexpression Inhibits Plaque Formation But Fails to Reduce Pathogenic A{beta} Oligomers and Associated Cognitive Deficits in Human Amyloid Precursor Protein Transgenic Mice J. Neurosci., February 18, 2009; 29(7): 1977 - 1986. [Abstract] [Full Text] [PDF]

				Q.-L. Ma, F. Yang, F. Calon, O. J. Ubeda, J. E. Hansen, R. H. Weisbart, W. Beech, S. A. Frautschy, and G. M. Cole p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis J. Biol. Chem., May 16, 2008; 283(20): 14132 - 14143. [Abstract] [Full Text] [PDF]

				W. J. Meilandt, G.-Q. Yu, J. Chin, E. D. Roberson, J. J. Palop, T. Wu, K. Scearce-Levie, and L. Mucke Enkephalin Elevations Contribute to Neuronal and Behavioral Impairments in a Transgenic Mouse Model of Alzheimer's Disease J. Neurosci., May 7, 2008; 28(19): 5007 - 5017. [Abstract] [Full Text] [PDF]

				W. S. Liang, T. Dunckley, T. G. Beach, A. Grover, D. Mastroeni, K. Ramsey, R. J. Caselli, W. A. Kukull, D. McKeel, J. C. Morris, et al. Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set Physiol Genomics, April 1, 2008; 33(2): 240 - 256. [Abstract] [Full Text] [PDF]

				H.-S. Hoe, S. S. Minami, A. Makarova, J. Lee, B. T. Hyman, Y. Matsuoka, and G. W. Rebeck Fyn Modulation of Dab1 Effects on Amyloid Precursor Protein and ApoE Receptor 2 Processing J. Biol. Chem., March 7, 2008; 283(10): 6288 - 6299. [Abstract] [Full Text] [PDF]

				D. V. Venkitaramani, J. Chin, W. J. Netzer, G. K. Gouras, S. Lesne, R. Malinow, and P. J. Lombroso {beta}-Amyloid Modulation of Synaptic Transmission and Plasticity J. Neurosci., October 31, 2007; 27(44): 11832 - 11837. [Full Text] [PDF]

				I. H. Cheng, K. Scearce-Levie, J. Legleiter, J. J. Palop, H. Gerstein, N. Bien-Ly, J. Puolivali, S. Lesne, K. H. Ashe, P. J. Muchowski, et al. Accelerating Amyloid-beta Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models J. Biol. Chem., August 17, 2007; 282(33): 23818 - 23828. [Abstract] [Full Text] [PDF]

				J. Chin, C. M. Massaro, J. J. Palop, M. T. Thwin, G.-Q. Yu, N. Bien-Ly, A. Bender, and L. Mucke Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease J. Neurosci., March 14, 2007; 27(11): 2727 - 2733. [Abstract] [Full Text] [PDF]

				V. M. Sharma, J. M. Litersky, K. Bhaskar, and G. Lee Tau impacts on growth-factor-stimulated actin remodeling J. Cell Sci., March 1, 2007; 120(5): 748 - 757. [Abstract] [Full Text] [PDF]

				H.-M. Yun, S. Kim, H.-J. Kim, E. Kostenis, J. I. Kim, J. Y. Seong, J.-H. Baik, and H. Rhim The Novel Cellular Mechanism of Human 5-HT6 Receptor through an Interaction with Fyn J. Biol. Chem., February 23, 2007; 282(8): 5496 - 5505. [Abstract] [Full Text] [PDF]

				J. Mojsilovic-Petrovic, G.-B. Jeong, A. Crocker, A. Arneja, S. David, D. Russell, and R. G. Kalb Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors J. Neurosci., September 6, 2006; 26(36): 9250 - 9263. [Abstract] [Full Text] [PDF]

				L. Esposito, J. Raber, L. Kekonius, F. Yan, G.-Q. Yu, N. Bien-Ly, J. Puolivali, K. Scearce-Levie, E. Masliah, and L. Mucke Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J. Neurosci., May 10, 2006; 26(19): 5167 - 5179. [Abstract] [Full Text] [PDF]

				V. Galvan, O. F. Gorostiza, S. Banwait, M. Ataie, A. V. Logvinova, S. Sitaraman, E. Carlson, S. A. Sagi, N. Chevallier, K. Jin, et al. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664 PNAS, May 2, 2006; 103(18): 7130 - 7135. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help