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Abstract
The two main pathological hallmarks of Alzheimer’s disease are amyloid plaques and neurofibrillary tangles. There is evidence supporting the hypothesis that the accumulation of Aβ, which makes up the core of amyloid plaques, triggers subsequent hyperphosphorylation of tau, leading to the formation of neurofibrillary tangles. However, the molecular mechanisms underlying the connection between Aβ and tau pathologies remain unclear. Fyn is a tyrosine kinase upregulated in Alzheimer’s disease which co-localizes with phosphorylated tau and neurofibrillary tangles. Recent studies have also implicated a role for Fyn in Aβ-mediated neurotoxicity. However, whether Fyn directly leads to the phosphorylation of tau, or to alteration in amyloid precursor protein (APP) processing to generate Aβ, is unknown.
We first investigated the effect of Fyn on APP processing and whether this effect is mediated through Dab1, an adaptor protein which is phosphorylated by Fyn and decreases Aβ production. Using in vitro culture models (COS7) and Fyn knock-out mice, we found that Fyn increases cell surface APP and promotes α-secretase processing of APP, in part through Dab1. We next determined the subcellular localization of the APP-Dab1-Fyn interactions using lipid raft isolation from brains and primary neurons, and found that Fyn mediates the interaction between APP and Dab1 by regulating their phosphorylation and localization in lipid rafts. Finally, we aimed to determine the effect of Fyn inhibition on pathological and behavioral symptoms in a triple transgenic (3xTg) model of Alzheimer’s disease if Fyn exerts opposing effects on Aβ production and tau phosphorylation. We found that genetic and pharmacological inhibition of Fyn in 3xTg mice resulted in a decrease in tau phosphorylation and an increase in Aβ production accompanied by a deficit in spatial learning. These effects were age and/or pathology dependent, underscoring the importance of considering age and/or disease burden when determining appropriate treatment. In conclusion, we establish a complex role for Fyn in mediating both APP processing and tau phosphorylation in a physiological environment as well as under the pathological conditions of Alzheimer’s disease.
