Figure 2

Examples of autophagic and endosomal dysfunction in Alzheimer’s disease (AD). (a) Decreased expression and activity of autophagy-inducing molecules (for example, beclin 1 and Atg proteins) or increased activity of autophagy suppressers – for example, mammalian target of rapamycin (mTOR) – inhibit autophagy induction. (b) In advanced AD, neurons contain high levels of autophagic vacuoles containing undigested content with elevated levels of inactive cathepsin indicative of improper lysosomal fusion or lysosomal pH or both. Intermediate vacuole accumulation may upregulate autophagy induction as an attempt to restore autophagy. (c) Presenilin dysfunction alters vacuole:lysosomal fusion possibly by increasing pH or decreasing calcium stores, resulting in an accumulation of autophagic and endosomal vacuoles. (d) Improper endosome-lysosome fusion, or elevated amyloid precursor protein (APP) alone, alters endosomal pathway function, culminating in high concentrations of enlarged endocytic vacuoles enriched with presenilin 1 (PS1) and APP capable of generating amyloid-beta peptides. LC3, autophagosome-bound phosphatidylethanolamine-conjugated microtubule-associated protein light chain 3.