| First Author | Keilani S | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 15 | Pages | 5223-36 |
| PubMed ID | 22496568 | Mgi Jnum | J:184450 |
| Mgi Id | MGI:5424056 | Doi | 10.1523/JNEUROSCI.4860-11.2012 |
| Citation | Keilani S, et al. (2012) Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-beta peptide. J Neurosci 32(15):5223-36 |
| abstractText | 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-beta peptide (Abeta)-like, alpha-synuclein-like, and phospho-tau-like immunoreactivity in the brains of beta-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Abeta-like immunoreactivity (iAbeta-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Abeta. In addition, we observed increased levels of Abeta40 and Abeta42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Abeta (GAbeta) immunoreactivity in a brain region-specific manner. Furthermore, alpha-synuclein and APP-CTFs and/or Abeta 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 iAbeta-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAbeta-LIR may be associated with the lysosomal-autophagic turnover of Abeta and fragments of APP-containing Abeta epitopes. Importantly, intraneuronal GAbeta 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. |
