Neurodegeneration in Alzheimer Disease: Role of Amyloid Precursor Protein and Presenilin 1 Intracellular Signaling

Figure 1

Schematic representation of AβPP processing, the adaptor proteins interacting with its intracellular domain and the pathway leading to ERK1/2 activation. In the left panels is reported the transmembrane protein APP, before and after ITS sequential beta secretase (BACE) and gamma secretase cleavage, with its final products, AICD, APP ectodomain, and beta amyloid peptide (1–40/1–42). In the right part of the figure are indicated the protein interacting with APP intracellular domain, upon or independently from tyrosine phosphorylation. The adaptor proteins Shc and Grb2 through their phosphotyrosine-binding domain (PTB) and src homology domain (SH2) are able to directly bind tyrosine-phosphorylated APP, resulting in the recruitment of the components of the MAP kinase cascade (SoS, ras, Raf, MEK) leading to ERK1/2 activation. Grb2 may participate in this pathway either by direct binding to APP or being recruited by Shc. Alteration in ERK1/2 activity induced in this way may contribute to neurodegeneration in AD. Transduction pathway adaptors (X11, disabled, Fe65, JIP1, and Numb) that bind APP in the absence of tyrosine phosphorylation depicted are also shown.