Evidence for hippocampal globotriaosylceramide (Gb3) accumulation and spatial memory impairment in a mouse model of Fabry disease

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene that reduce α-galactosidase A activity and lead to progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids. In the human brain, Gb3 deposition is reported predominantly within the endothelium of small cerebral vessels and is associated with cerebrovascular dysfunction, seizures, cognitive impairment, and neuropsychiatric symptoms. In experimental animal models, its regional distribution, cellular localization, and relationship to cognitive dysfunction remain incompletely defined and appear to vary according to species, model, age, disease severity, and detection method.Here, using the α-galactosidase A hemizygous knockout mouse (α-Gal A −/0) and immunofluorescence, we performed a regional and cell-type-specific characterization of Gb3 immunoreactivity in the hippocampus and assessed hippocampal-dependent spatial learning and memory. Compared with wild-type controls (α-Gal A +/0), α-Gal A −/0 mice showed a marked increase in hippocampal Gb3 immunoreactivity, with deposits localized mainly to vascular endothelial cells and frequent signal within the capillary lumen. Neuronal Gb3 signal was detected in dentate gyrus hilar neurons with mossy cell-like morphology. Gb3 did not overlap with astrocytic (GFAP) or microglial (Iba1) markers, although astrocytic endfeet and activated microglia were often apposed to Gb3-positive vessels. In parallel, α-Gal A (−/0) mice displayed impaired Morris water maze acquisition and reduced spatial memory during the probe trial, without changes in swimming speed or distance. These data suggest that α-Gal A deficiency is associated with increased hippocampal Gb3 immunoreactivity, mainly in neurovascular compartments, and with measurable impairment in spatial memory.