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Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-β
Serene Keilani1, Yi Lun, Anthony C Stevens
1Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
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.
Insights
GM2 ganglioside accumulation in Sandhoff disease models correlates with the buildup of Alzheimer's disease (AD)-associated proteins like amyloid-beta and tau. This suggests a link between ganglioside metabolism, autophagy, and AD pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Lipid alterations in endosomal-lysosomal membranes may precede Alzheimer's disease (AD) development.
- GM2 ganglioside accumulation is a hallmark of lysosomal storage disorders like Sandhoff disease.
Purpose of the Study:
- To investigate if GM2 ganglioside accumulation in Sandhoff disease models is linked to the buildup of AD-associated proteins.
- To explore the relationship between gangliosides, autophagy, and protein aggregation in neurodegenerative conditions.
Main Methods:
- Utilized a mouse model of Sandhoff disease (β-hexosaminidase knock-out, HEXB KO).
- Performed biochemical and immunohistochemical analyses to detect protein aggregates.
- Examined postmortem human brains from GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease patients.
Main Results:
- Intraneuronal accumulation of amyloid-β peptide (Aβ)-like, α-synuclein-like, and phospho-tau-like proteins observed in HEXB KO mice.
- Confirmed intraneuronal Aβ-like immunoreactivity (iAβ-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Aβ.
- Found increased levels of Aβ40 and Aβ42 peptides in lipid-associated fractions and intraneuronal ganglioside-bound Aβ (GAβ) accumulation in HEXB KO mice.
- Observed intraneuronal GAβ accumulation in human brains with lysosomal storage disorders.
Conclusions:
- GM2 ganglioside accumulation is associated with the buildup of AD-related proteins, including Aβ, α-synuclein, and tau.
- Lysosomal-autophagic pathways are implicated in the turnover of Aβ and APP fragments, with impaired ganglioside metabolism potentially disrupting these processes.
- Findings suggest a potential link between gangliosidoses, autophagic dysfunction, and the intraneuronal accumulation of proteins relevant to AD pathogenesis.
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