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The Journal of Neuroscience, May 12, 2004, 24(19):4692-4697; doi:10.1523/JNEUROSCI.0277-04.2004

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Neurobiology of Disease
Fyn Kinase Modulates Synaptotoxicity, But Not Aberrant Sprouting, in Human Amyloid Precursor Protein Transgenic Mice

Jeannie Chin,¹ Jorge J. Palop,¹ Gui-Qiu Yu,¹ Nobuhiko Kojima,² Eliezer Masliah,³ and Lennart Mucke¹

¹Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, California 94141, ²Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Wako 351-0198, Japan, and ³Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, California 92093

Alzheimer's disease (AD), the most common neurodegenerative disorder, results in progressive degeneration of synapses and aberrant sprouting of axon terminals. The mechanisms underlying these seemingly opposing cellular phenomena are unclear. We hypothesized that Fyn kinase may play a role in one or both of these processes because it is increased in AD brains and because it is involved in synaptic plasticity and axonal outgrowth. We investigated the effects of Fyn on AD-related synaptotoxicity and aberrant axonal sprouting by ablating or overexpressing Fyn in human amyloid precursor protein (hAPP) transgenic mice.

On the fyn^+/+ background, hAPP/amyloid peptide (A) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On the fyn^-/- background, hAPP/A did not affect SIPTs. SIPT reductions correlated with hippocampal A levels in hAPP/fyn^+/+, but not hAPP/fyn^-/-, mice suggesting that Fyn provides a critical link between hAPP/A and SIPTs. Furthermore, overexpression of Fyn exacerbated SIPT reductions in hAPP mice. We also found that the susceptibility of mice to hAPP/A-induced premature mortality was decreased by Fyn ablation and increased by Fyn overexpression. In contrast, axonal sprouting in the hippocampus of hAPP mice was unaffected. We conclude that Fyn-dependent pathways are critical in AD-related synaptotoxicity and that the pathogenesis of hAPP/A-induced neuronal alterations may be mechanistically heterogenous.

Key words: Alzheimer's disease; amyloid ; Fyn kinase; synaptic deficits; signaling; sprouting; GAP-43; neurodegeneration

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Received Jan 23, 2004; revised April 8, 2004; accepted April 9, 2004.

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