Figure 1.

Potential cellular and molecular mechanisms of chloroquine in neurodegeneration. The lysosomotropic agent chloroquine (CQ) rapidly penetrates across lipid bilayer membranes and following a pH gradient accumulates within lysosomes. In these acidic organelles, CQ behaves as a weak base by increasing the pH, which in turns affects the activity of lysosomal hydrolases. Disruption of lysosomal activity prevents interaction and fusion among organelles of the autophagy-lysosome and of the endocytic pathways. This cellular condition may have dichotomic effects in the pathogenesis of neurodegenerative diseases by (A) inhibiting cytosolic clearance of aberrantly protein fibrils and (B) preventing MHC class II-mediated antigen presentation and preventing the expression of pro-inflammatory cytokines via TLR activation.