Lysosomal Dysfunction in a Mouse Model of Sandhoff Disease Leads to Accumulation of Ganglioside-Bound Amyloid-β Peptide

作者：Serene Keilani, Yi Lun, Anthony C. Stevens, Hadis Williams, Eric R. Sjoberg, Richie Khanna, Kenneth J. Valenzano, Frédéric Checler, Joseph D. Buxbaum, Katsuhiko Yanagisawa, David J. Lockhart, Brandon A. Wustman, Sam Gandy · 发表于：Journal of Neuroscience · 年份：2012 · DOI：10.1523/jneurosci.4860-11.2012 · 被引用次数：105 · 研究领域：Lysosomal Storage Disorders Research、Alzheimer's disease research and treatments、Cellular transport and secretion

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-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/or Aβ. In addition, we observed 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-specific manner. Furthermore, α-synuclein and APP-CTFs and/or Aβ 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 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 immunor...