title: Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β peptide.
abstract: 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 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.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Serene
authors.initials: S
authors.lastname: Keilani
authors.forename: Yi
authors.initials: Y
authors.lastname: Lun
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Stevens
authors.forename: Hadis N
authors.initials: HN
authors.lastname: Williams
authors.forename: Eric R
authors.initials: ER
authors.lastname: Sjoberg
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: Frederic
authors.initials: F
authors.lastname: Checler
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Wustman
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D002675:Child, Preschool; D005678:G(M2) Ganglioside / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism*; D054819:Hexosaminidase B / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D050356:Lipid Metabolism; D008247:Lysosomes / Q000502:physiology*; D008526:Medulla Oblongata / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012497:Sandhoff Disease / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D055815:Young Adult; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005732:Gangliosides; D051844:alpha-Synuclein; D016875:tau Proteins; D005678:G(M2) Ganglioside; D054819:Hexosaminidase B