Abstract
BackgroundGangliosides are highly enriched in the brain and are critical for its normal development and function. However, in some rare neurometabolic diseases, a deficiency in lysosomal ganglioside hydrolysis is pathogenic and leads to early-onset neurodegeneration, neuroinflammation, demyelination, and dementia. Increasing evidence also suggests that more subtle ganglioside accumulation contributes to the pathogenesis of more common neurological disorders including Alzheimer’s disease (AD). Notably, ganglioside GM3 levels are elevated in the brains of AD patients and in several mouse models of AD, and plasma GM3 levels positively correlate with disease severity in AD patients.MethodsTg2576 AD model mice were fed chow formulated with a small molecule inhibitor of glucosylceramide synthase (GCSi) to determine whether reducing glycosphingolipid synthesis affected aberrant GM3 accumulation, amyloid burden, and disease manifestations in cognitive impairment. GM3 was measured with LC-MS, amyloid burden with ELISA and amyloid red staining, and memory was assessed using the contextual fear chamber test.ResultsGCSi mitigated soluble Aβ42 accumulation in the brains of AD model mice when treatment was started prophylactically. Remarkably, GCSi treatment also reduced soluble Aβ42 levels and amyloid plaque burden in aged (i.e., 70 weeks old) AD mice with preexisting neuropathology. Our analysis of contextual memory in Tg2576 mice showed that impairments in remote (cortical-dependent) memory consolidation preceded deficits in short-term (hippocampal-dependent) contextual memory, which was consistent with soluble Aβ42 accumulation occurring more rapidly in the cortex of AD mice compared to the hippocampus. Notably, GCSi treatment significantly stabilized remote memory consolidation in AD mice—especially in mice with enhanced cognitive training. This finding was consistent with GCSi treatment lowering aberrant GM3 accumulation in the cortex of AD mice.ConclusionsCollectively, our results indicate that glycosphingolipids regulated by GCS are important modulators of Aβ neuropathology and that glycosphingolipid homeostasis plays a critical role in the consolidation of remote memories.
Highlights
Gangliosides are highly enriched in the brain and are critical for its normal development and function
We found that glucosylceramide synthase (GCSi) treatment in Tg2575 mice reduced brain GM3 levels to WT levels, lowered soluble Aβ with 42 amino acid peptides (Aβ42), which is toxic to neurons [13] and a determinant of disease severity in Alzheimer disease (AD) patients [33], and improved remote memory consolidation
Despite sex-differences in cognitive behavior we did not find any sex-differences in the rate of Amyloid beta (Aβ) species accumulation in the cortex, hippocampus, or amygdala of Tg2576 at either 20 or 36 weeks (Fig. S1)
Summary
Gangliosides are highly enriched in the brain and are critical for its normal development and function. Increasing evidence suggests that more subtle ganglioside accumulation contributes to the pathogenesis of more common neurological disorders including Alzheimer’s disease (AD). Several lines of evidence suggest that more subtle ganglioside accumulation contributes to the pathogenesis of Alzheimer disease (AD), the most common form of dementia. Cross-breeding mice deficient in either GlcCer synthase or GM3 synthase with AD model mice mitigates the manifestation of Aβ-associated neuropathology and cognitive deficits [4, 17, 21]. It remains unknown, whether reducing ganglioside levels in symptomatic AD mice with preexisting Aβ accumulation will slow disease pathogenesis
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