Lysosomal dysfunction in a mouse model of sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide

Serene Keilani, Yi Lun, Anthony C. Stevens, Hadis N. Williams, Eric R. Sjoberg, Richie Khanna, Kenneth J. Valenzano, Frederic Checler, Joseph D. Buxbaum, Katsuhiko Yanagisawa, David J. Lockhart, Brandon A. Wustman, Sam Gandy

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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 thatGM2ganglioside 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-β peptide (Aβ)-like, α-synuclein-like, and phospho-tau-like immunoreactivity in the brains of β-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Aβ-like immunoreactivity (iAβ-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/orAβ. Inaddition,weobserved increased levels of Aβ40 and Aβ42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Aβ (GAβ) immunoreactivity in a brain region-specificmanner.Furthermore, β-synucleinand APP-CTFsand/or Aβ werefoundto accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAβ-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAβ-LIR may be associated with the lysosomal-autophagic turnover of Aβ and fragments of APP-containing Aβ epitopes. Importantly, intraneuronal GAβ 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.

Original languageEnglish
Pages (from-to)5223-5236
Number of pages14
JournalJournal of Neuroscience
Issue number15
StatePublished - 11 Apr 2012


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