Accelerated Aβ Generation in a Cell Model of Alzheimer's Disease‐related Endosomal–Lysosomal System Upregulation

We have previously identified and characterized prominent endosomal and lysosmal changes with neurons, changes that are an invariant and early feature of sporadic Alzheimer's disease. Lysosomal system activation, which develops in virtually all neurons within at‐risk populations, is characterized by increased gene expression and protein expression of lysosomal hydrolases, including such proteases as cathepsin D, and a robust increase in the number of lysosmes. Neuronal endocytic abnormalities precede substantial β‐amyloid deposition in Alzheimer's disease brain and begin even decades prior to the development of Alzheimer's disease pathology in Down's syndrome. Endocytic pathway abnormalities in Alzheimer's disease include increased early endosome volume, increased expression of proteins involved in the regulation of endocytosis and recycling and abnormally increased levels of lysosomal hydrolases within the early endosome.