Glucosylceramide synthase inhibition reduces ganglioside GM3 accumulation, alleviates amyloid neuropathology, and stabilizes remote contextual memory in a mouse model of Alzheimer’s disease

Abstract

Background Gangliosides 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. Methods Tg2576 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. Results GCSi 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. Conclusions Collectively, 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.

Circulating lipid profiles are associated with cross-sectional and longitudinal changes of central biomarkers for Alzheimer’s disease

“…In a mouse model study, the reduction of G M3 ganglioside by inhibition of glucosylceramide synthase resulted in stabilized remote memory and lower soluble Aβ in the brain. 63 A previous human study showed that increased levels of the G M3 ganglioside species were associated with incident or prevalent AD. 8 Thus, our findings regarding these classes are in line with these reports, supporting the evidence for their potential roles in AD pathogenesis.…”

Behavioral, metabolic, and lipidomic characterization of the 5xFADxTg30 mouse model of Alzheimer’s disease

“…One recent study demonstrated alleviation of neuropathology in transgenic mice when treated with inhibitors within the GM3 pathway. 49 In the brain of male mice, total diacylglycerol pool was elevated, in contrast to the plasma where it was reduced. Diacylglycerol has been shown to be elevated in the frontal cortex of patients with AD, 50 , 51 however, why there is a sex difference and opposing results between plasma and brain in our model is unknown.…”

Double‐Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α‐Synuclein

“…Venglustat had no apparent effects in the Y‐maze test and ameliorated an endophenotype in the NOR test, probably through reduction of a heightened anxiety‐like state in Thy1‐aSyn mice. This should raise caution regarding the interpretation of previously reported cognitive benefits in other PD, GD, or Alzheimer's disease models that could have been influenced by similar behavioral changes 12,13,44 . The apparent disparity between different behavioral domains (ie, motor and nonmotor) argues for brain region–specific effects of venglustat.…”

“…This should raise caution regarding the interpretation of previously reported cognitive benefits in other PD, GD, or Alzheimer's disease models that could have been influenced by similar behavioral changes. 12,13,44 The apparent disparity between different behavioral domains (ie, motor and nonmotor) argues for brain region-specific effects of venglustat. Indeed, venglustat tended to increase α-synuclein pathology and microgliosis in the SN of Thy1-aSyn mice but appeared to be neuroprotective in limbic brain regions, as reported previously in the hippocampus of PD/GD models.…”