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

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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)

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

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