Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloid-? peptide (A?)-like, ?-synuclein-like, and phospho-tau-like immunoreactivity in the brains of ?-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal A?-like immunoreactivity (iA?-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or A?. In addition, we observed increased levels of A?40 and A?42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound A? (GA?) immunoreactivity in a brain region-specific manner. Furthermore, ?-synuclein and APP-CTFs and/or A? were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iA?-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iA?-LIR may be associated with the lysosomal-autophagic turnover of A? and fragments of APP-containing A? epitopes. Importantly, intraneuronal GA? immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD.