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 ϩ/ϩ background, hAPP/amyloid  peptide (A) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On the fyn Ϫ/Ϫ background, hAPP/A did not affect SIPTs. SIPT reductions correlated with hippocampal A levels in hAPP/fyn ϩ/ϩ , but not hAPP/fyn Ϫ/Ϫ , 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
IntroductionThe amyloid precursor protein (APP) is expressed in many cell types and is particularly abundant in synapses. One of its metabolites, amyloid  peptide (A), suppresses synaptic transmission and may participate in the regulation of neuronal activity (Hsia et al., 1999;Kamenetz et al., 2003). Mutations in the human APP (hAPP) gene that lead to increased levels of A cause autosomal dominant familial Alzheimer's disease (FAD) (Selkoe and Schenk, 2003). Of several species of A produced, the 42-residue form (A1-42) is particularly susceptible to aggregation and is a primary constituent of neuritic amyloid plaques, pathological hallmarks of the disease (Selkoe and Schenk, 2003). Both FAD and sporadic AD are associated with a progressive degeneration of neurons and synapses (DeKosky and Scheff, 1990;Terry et al., 1999) and an aberrant sprouting of axon terminals (Geddes et al., 1985;Masliah et al., 1991;Arendt, 2001). The precise relationship between hAPP, A, plaques, synaptic loss, axonal sprouting, and cognitive decline in AD is unknown.Although amyloid plaques are a diagnostic feature of AD, growing evidence suggests that plaques may not be the primary cause of AD-related synaptic alterations and cognitive decline. In transgenic (TG) mice overexpressing hAPP/A in neurons, synaptic and behavioral deficits are detectable well before plaque formation (Holcomb et al., 1999;Hsia et al., 199...