Abstract

Significance Amyloid plaques, a key feature of Alzheimer’s disease brain pathology, comprise an extracellular β-amyloid core surrounded by tissue enriched in lysosome-like organelles. As a foundation for understanding the mechanisms that drive amyloid plaque formation, we have elucidated the cellular origins and molecular composition of such organelles. The majority of the lysosomes at amyloid plaques reside within swollen neuronal axons. Interestingly, these organelles contain low levels of multiple luminal lysosomal proteases and closely resemble a lysosome subpopulation that naturally occurs in distal neuronal processes. These results suggest that extracellular β-amyloid deposits cause a local impairment in retrograde axonal transport, leading to the accumulation of lysosome precursors and a blockade in their further maturation that has implications for both β-amyloid production and clearance.