Deletion of Specific Sphingolipids in Distinct Neurons Improves Spatial Memory in a Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and a concomitant loss of synapses and cognitive abilities. Recently, we have proposed that an alteration of neuronal membrane lipid microdomains increases neuronal resistance toward amyloid-β stress in cultured neurons and protects from neurodegeneration in a mouse model of AD. Lipid microdomains are highly enriched in a specific subclass of glycosphingolipids, termed gangliosides. The enzyme glucosylceramide synthase (GCS) catalyzes the rate-limiting step in the biosynthesis of these gangliosides. The present work now demonstrates that genetic GCS deletion in subsets of adult forebrain neurons significantly improves the spatial memory and counteracts the loss of dendritic spines in the hippocampal dentate gyrus of 5x familial AD mice (5xFAD//Ugcgf/f//Thy1-CreERT2//EYFP mice), when compared to 5xFAD//Ugcgf/f littermates (5xFAD mice). Aberrantly activated glial cells and their expression of pro-inflammatory cytokines have emerged as the major culprits for synaptic loss in AD. Typically, astrocytic activation is accompanied by a thickening of astrocytic processes, which impairs astrocytic support for neuronal synapses. In contrast to 5xFAD mice, 5xFAD//Ugcgf/f//Thy1-CreERT2//EYFP display a less pronounced thickening of astrocytic processes and a lower expression of tumor necrosis factor-α and interleukin 1-α in the hippocampus. Thus, this work further emphasizes that GCS inhibition may constitute a potential therapeutic target against AD.

Spatially resolved mass spectrometry analysis of amyloid plaque‐associated lipids

“…In line with the MS data, as important myelin sheath components, sulfatides depletion is linked to demyelination (Marcus et al, 2006) as well as to alterations in APOE and TREM2 activity in the AD brain (Cheng et al, 2010;Wang et al, 2015). AD brains also present altered gangliosides biosynthesis as reported previously (Ariga et al, 2008;Chan et al, 2012;Pernber et al, 2012) and its inhibition showed positive effects in memory function in AD mouse models (Bernardo et al, 2009;Herzer et al, 2018).…”

The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

“…Even at a low concentration, gangliosides create clusters that are relevant to lipid rafts [ 30 , 127 ]. Blocking of ganglioside synthesis leads to destruction of lipid rafts and increased cell viability in cultured neurons exposed to Aβ oligomers, as well as less neurodegeneration in the cerebral cortex and improved spatial memory in AD model mice [ 128 , 129 , 130 ].…”

Spatial Lipidomics Reveals Region and Long Chain Base Specific Accumulations of Monosialogangliosides in Amyloid Plaques in Familial Alzheimer’s Disease Mice (5xFAD) Brain

“…5xFAD transgenic mice develop cerebral amyloid plaques particularly in deep cortical layers and the hippocampus . Further, a number of amyloid-associated histopathological and/or molecular investigations have been performed on 5xFAD mice, including studies of plaque pathology in conjunction with lipid metabolism related immune proteins such as the microglial receptors, triggering receptor expressed on myeloid cells 2 (TREM2) and sialic acid binding immunoglobulin-like lectin 3 (CD33) as well as the studies of the genes involved in ganglioside metabolism. , For instance, Herzer et al demonstrated that genetic deletion of the enzyme glucosylceramide synthase (GCS), which catalyzes the rate-limiting step in the biosynthesis of gangliosides, significantly improves the spatial memory, lowers inflammation markers in the hippocampus, and counteracts the loss of dendritic spines in the hippocampal dentate gyrus (DG) in 5xFAD mice . This makes this mouse model an excellent target for MALDI-IMS analysis as the mass spectrometric data can be referenced to the wealth of other published findings.…”