{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:42:09Z","timestamp":1789188129590,"version":"build-2803163510"},"reference-count":53,"publisher":"Society for Neuroscience","issue":"15","license":[{"start":{"date-parts":[[2012,10,11]],"date-time":"2012-10-11T00:00:00Z","timestamp":1349913600000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2012,4,11]]},"abstract":"<jats:p>Alterations in the lipid composition of endosomal\u2013lysosomal 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-\u03b2 peptide (A\u03b2)-like, \u03b1-synuclein-like, and phospho-tau-like immunoreactivity in the brains of \u03b2-hexosaminidase knock-out (<jats:italic>HEXB<\/jats:italic>KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal A\u03b2-like immunoreactivity (iA\u03b2-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and\/or A\u03b2. In addition, we observed increased levels of A\u03b240 and A\u03b242 peptides in the lipid-associated fraction of<jats:italic>HEXB<\/jats:italic>KO mouse brains, and intraneuronal accumulation of ganglioside-bound A\u03b2 (GA\u03b2) immunoreactivity in a brain region-specific manner. Furthermore, \u03b1-synuclein and APP-CTFs and\/or A\u03b2 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\u03b2-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iA\u03b2-LIR may be associated with the lysosomal\u2013autophagic turnover of A\u03b2 and fragments of APP-containing A\u03b2 epitopes. Importantly, intraneuronal GA\u03b2 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\u2013Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD.<\/jats:p>","DOI":"10.1523\/jneurosci.4860-11.2012","type":"journal-article","created":{"date-parts":[[2012,4,11]],"date-time":"2012-04-11T16:29:13Z","timestamp":1334161753000},"page":"5223-5236","source":"Crossref","is-referenced-by-count":82,"title":["Lysosomal Dysfunction in a Mouse Model of Sandhoff Disease Leads to Accumulation of Ganglioside-Bound Amyloid-\u03b2 Peptide"],"prefix":"10.1523","volume":"32","author":[{"given":"Serene","family":"Keilani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C.","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadis 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