Alteration of β-secretase traffic by the receptor tyrosine kinase signaling pathway- a new mechanism for regulating Alzheimer's β-amyloid production

The receptor tyrosine kinases (RTKs) are a family of cellsurface proteins with diverse functions in proliferation, dif-ferentiation or cell-cell communication. When a specific li-gand binds to its cognate receptor, a conformational changeof this receptor due to the ligand-receptor interaction willlead to activation of the intrinsic tyrosine kinase residing inthe intracellular domain of the receptor. The activation ofthis tyrosine kinase is essential for transducing the signals toa cascade of its downstream molecules that eventually causerelated physiological responses 1]. For example, binding ofnerve growth factor (NGF) to its receptor TrkA is essentialfor the proper development, patterning, and maintenanceof the mammalian nervous system. This ligand and recep-tor interaction will lead to the formation of a crab-shapedhomodimeric TrkA structure 2], and the subsequent activa-tion of its intrinsic RTK will cause auto-phosphorylationof its own intracellular tyrosine residues. PhosphorylatedTrkA receptors recruit and increase the phosphorylationof PLC-γ and Shc, which leads to activation of either thePI3K/Akt pathway or Ras/raf/ERK pathway. In the brainOf Alzheimer's disease (AD) patients, alterations of nervegrowth factor (NGF) and its receptor TrkA have beenreported to associate with AD pathogenesis 3]. However,the underlying mechanisms remain elusive.