Amyloid- (A) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for A processing and secretion. In Alzheimer's disease (AD), dysregulation of APP leads to excess A and neuronal dysfunction; suggesting that neuronal APP/A trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower A levels. However, whether CatB-modulation of A improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced A levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed A metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.