Alzheimer's disease (AD) is the most common cause of dementia and rising healthcare costs in Europe and the United States. Growing evidence supports a link between glycosphingolipid metabolism and neurodegenerative diseases such as Alzheimer's and Parkinson's. For instance, heterozygous mutations in £]-glucocerebrosidase, a lysosomal enzyme required for the final step of sphingolipid catabolism, represent the most prevalent risk factor for developing Parkinson's disease and other Lewy body diseases. In further support of a link between glycosphingolipid metabolism and neurodegeneration, we have identified animal models with impaired glycosphingolipid metabolism that develop an AD-like pathology. Additionally, we have found that human fibroblasts with impaired ganglioside catabolism demonstrate altered APP processing and tau phosphorylation, two biochemical hallmarks of AD. Our results are consistent with previous studies which indicated that gangliosides may contribute to the pathogenesis of Alzheimer's disease by accelerating the generation of neurotoxic forms of A£] in the brain. Thus, reducing ganglioside levels by increasing the activity of enzymes involved in ganglioside catabolism represents a novel therapeutic approach to the treatment of Alzheimer's disease. Pharmacological chaperones (PCs) are small molecules that specifically enhance cellular levels (and functional activity) of a target protein by promoting proper folding, reducing premature degradation, and increasing the efficiency of endoplasmic reticulum export. We have found that the PC AT3150 can selectively increase the activity of an enzyme involved in ganglioside catabolism in the brains of C57BL6 mice. The goal of the proposed research plan is to test whether pharmacological chaperones that are known to increase ganglioside catabolism can impact (i.e., delay or prevent) the accumulation of human A£], human tau, and the attendant behavioral deficits in APP and TAU transgenic mouse models.