Physiological Production and Polarized Secretion of the Amyloid β-Peptide in Epithelial Cells: A Route to the Mechanism of Alzheimer’s Disease

Summary

Converging evidence from many laboratories has implicated altered metabolism of the amyloid β protein precursor (βAPP) and progressive deposition of its amyloid β-peptide (Aβ) fragment as an early and constant feature of the pathogenesis of Alzheimer’s disease. βAPP is a widely expressed type I integral membrane glycoprotein that undergoes processing by two principal routes: exocytic (secretory) and endocytic (reinternalization and lysosomal targeting). Either or both of these routes is capable of generating the intact Aβ fragment following cleavages by as yet unknown proteases. This leads to constitutive secretion of Aβ as a soluble peptide from a variety of neural and non-neural cells that express βAPP. One compartment in which Aβ generation appears to occur is the early endosome. Studies of βAPP trafficking in polarized epithelial cells grown in monolayer cultures suggests that Aβ is generated at least in part from βAPP molecules that traffic asymmetrically to the cell surfaces, with the major portion of Aβ being released from the basolateral surface. These and other studies of the detailed cellular mechanism for generation of Aβ should provide insights into specifically inhibiting cellular production and secretion of Aβ as a therapeutic approach toward slowing the progression of Alzheimer’s disease.