Autophagic/lysosomal dysfunction in Alzheimer's disease

Abstract

Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.

Figure 1

Healthy neurons execute highly efficient autophagy. (a) Autophagy induction begins with phagophore formation, which requires LC3 and Atg proteins. (b) As induction proceeds, the phagophore membrane elongates while continuing to recruit cytosolic proteins and organelles. As the phaogphore membrane closes, Atg proteins dissociate. The final encapsulated vacuole is now called an autophagosome. (c) Autophagosomes fuse with lysosomes, and LC3 proteins dissociate from the membrane. (d) The resulting autolysosome contains active acidic hyrdolases that degrade enclosed cytosolic content. Neurons contain more abundant cathepsin-positive autolysosomes. (e) Autophagy completion is marked by digestion of the autophagosome and autophagosomal content and the release of amino acids and other metabolic products. APP, amyloid precursor protein; LC3, autophagosome-bound phosphatidylethanolamine-conjugated microtubule-associated protein light chain 3; PS1, presenilin 1.

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.