The impact of sulfatide loss on the progress of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurogenerative disorder associated with age, marked by a gradual decline in memory, cognitive impairment, and behavioral changes. Among its key pathological traits is the presence of extracellular neuritic plaques enriched in β-amyloid, coupled with a decline in neuronal synapses and an accumulation of lipid granules.

Within the brain, myelinating glial cells play a crucial role in providing electrical insulation and facilitating the swift propagation of action potential along neuronal axons. Approximately 80% of myelin’s dry weight is composed of lipids¹, which not only establish an optimal membrane fluidity but also provide the essential hydrophobic insulation required for effective action potential conduction. The composition of myelin lipids includes cholesterol, phospholipids, and sphingolipids. Among sphingolipids, sphingomyelin (SM), ceramides, and sulfatide (ST) stand out as prominent enriched constituents within myelin membranes¹. Sulfatide, predominantly located at the outer leaflet of the cell membrane across all eukaryotic cells, is associated with a variety of cellular processes including platelet aggregation, cell survival, immune responses, and host-pathogen interactions². The enzyme cerebroside sulfotransferase, located within the Golgi apparatus, catalyzes the conversion of galactocerebroside into ST, whereas the turnover of ST is mediated by the lysosomal arylsulfatase/saposin B complex². Lipidomic and metabolomic studies reveal disrupted lipid metabolism in early stages of individuals with AD, evidenced by reduced ST levels [e.g.,³] and by near-total depletion of the sphingolipid in the brains of deceased individuals with AD⁴.

Accumulating evidence underscores the role of glia-mediated inflammation as a major contributor to the progression of AD, including cognitive shortfalls⁵. In mice where the enzyme cerebroside sulfotransferase is conditionally knocked out, the loss of ST in the central nervous system triggers the activation of microglia and astrocytes associated with AD, the upregulation of AD-related genes, and the modulation of the immune/microglia network, all of which promote cognitive deficits and neuroinflammation⁶. Another major player that is impacted by ST deficiency is apolipoprotein E (ApoE), which participates in the transport of ST to brain cells⁷. Sulfatide-loaded ApoE is recognized by members of the LDL receptor superfamily, leading to most ST molecules undergoing degradation within late endosomal and lysosomal compartments. The deposition of β-amyloid, resulting from the breakdown of the amyloid protein precursor, serves as a hallmark of AD. The association of ApoE to ST facilitates β-amyloid clearance via an endocytic pathway⁸. Experiments carried out using a knockout mice model with deficient levels of ST have revealed that the expression of the ApoE gene is upregulated as a compensatory response to the loss of ST; however, the increased ApoE levels do not trigger the activation of astrocytes and microglia⁶.

The spinal cord serves as a bridge between the central nervous system to the rest of the body. Clinical dysfunction of the spinal cord has shown associations with patients affected by AD. The degeneration of the spinal cord has been proposed as an internal marker for AD-related dementia⁹. Moreover, spinal cord injury has been identified as a factor that increases susceptibility to the development of AD¹⁰. In a recent publication by Xianlin Han and his team, new insights into the impact of ST loss on the progression of AD have emerged. Using shotgun lipidomics, the authors have pinpointed a decrease in the overall lipid content within the spinal cords of AD individuals when compared to the lipid composition observed in the spinal cords of those with normal cognitive function¹¹. The impact of these changes was more pronounced in white matter compared to grey matter. The reduction in ST levels within myelin lipids extracted from AD patients was remarkable and displayed a correlation with increased severity of tau-associated AD pathology. Alongside the total decline in lipid content, changes in the levels of specific proteins were also detected in the spinal cords of AD patients. For instance, the destabilization of myelin sheath in AD spinal cords was reflected through a reduction in the levels of myelin-associated oligodendrocyte basic protein, whereas activation of the microglia in these samples was evident by the elevated expression of the microglial marker allograft inflammatory factor 1.

Lower urinary tract dysfunction, such as urinary incontinence, tends to manifest during the middle to late stages of AD patients, yet the underlying cause remains elusive. To underpin their findings in AD spinal cords and establish a mechanistic rationale for AD-associated urinary incontinence, Han and colleagues utilized a mouse model deficient in cerebroside sulfotransferase, the enzyme responsible for ST synthesis. The reduction of the total lipid content seen in these mice concurred with the measurements observed in the spinal cords of AD patients. Likewise, changes in the levels of proteins associated with AD were apparent, mirroring the neuroinflammation patterns observed in AD individuals. In the AD mice model, the urinary bladder was found to be enlarged and heavier in comparison to control mice. Despite having comparable water intake among all mice, those in the AD model displayed a reduced daily urine volume, suggesting a possible connection with their enlarged bladder size. The enlarged bladder was specifically correlated to the impaired function of the central nervous system, a characteristic feature of neurogenic bladder.

Through transcriptome analysis of differentially expressed genes, Han and colleagues demonstrated that the loss of ST in both human AD and the mouse AD model spinal cords prompts enhanced inflammatory responses, accompanied with a deterioration in the function of neurons and oligodendrocytes. Furthermore, in both human AD and the mouse AD model spinal cords, the loss of ST led to the expression of the gene encoding phospholipase C γ2. This membrane-binding enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate, resulting in the production of diacylglycerol and inositol 1,4,5-trisphosphate. These molecules serve as second messengers in pathways that regulate cell survival and cytokine production. Indeed, elevated levels of cytokines were observed in both human AD and mouse AD model spinal cords.

Substantial evidence in the literature underscores the pivotal role of ST in maintaining proper neuronal function and its loss is associated to the onset and progression of AD. The study conducted by Han and colleagues not only supports these notions but also provides insights into the implications of decreased ST levels in both individuals with AD and through the use of an AD mouse model. These deficits are concomitant with alterations in the regulation of proteins implicated in neural function and lipid metabolism, alongside the manifestation of bladder dysfunction. The novel insights gathered from these findings hold promise for shaping future therapeutic strategies aimed at ameliorating the lives of individuals suffering AD.