Alterations in the metabolism of amyloid precursor protein (APP) are believed to 
play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate 
that APP is proteolytically processed in endosomal-autophagic-lysosomal 
compartments. In this study, we used both in vivo and in vitro paradigms to 
determine whether alterations in macroautophagy affect APP metabolism. Three 
mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, 
GM1 gangliosidosis, and Sandhoff disease, had mTOR-independent increases in the 
autophagic vacuole (AV)-associated protein, LC3-II, indicative of impaired 
lysosomal flux. APP C-terminal fragments (APP-CTFs) were also increased in 
brains of the three mouse models; however, discrepancies between LC3-II and 
APP-CTFs were seen between primary (GM1 gangliosidosis and Sandhoff disease) and 
secondary (Niemann-Pick type C1) lysosomal storage models. APP-CTFs were 
proportionately higher than LC3-II in cerebellar regions of GM1 gangliosidosis 
and Sandhoff disease, although LC3-II increased before APP-CTFs in brains of 
NPC1 mice. Endogenous murine Aβ40 from RIPA-soluble extracts was increased in 
brains of all three mice. The in vivo relationship between AV and APP-CTF 
accumulation was also seen in cultured neurons treated with agents that impair 
primary (chloroquine and leupeptin + pepstatin) and secondary (U18666A and 
vinblastine) lysosomal flux. However, Aβ secretion was unaffected by agents that 
induced autophagy (rapamycin) or impaired AV clearance, and LC3-II-positive AVs 
predominantly co-localized with degradative LAMP-1-positive lysosomes. These 
data suggest that neuronal macroautophagy does not directly regulate APP 
metabolism but highlights the important anti-amyloidogenic role of lysosomal 
proteolysis in post-secretase APP-CTF catabolism.