Academic Journal
Evidence for hippocampal globotriaosylceramide (Gb3) accumulation and spatial memory impairment in a mouse model of Fabry disease.
| Τίτλος: | Evidence for hippocampal globotriaosylceramide (Gb3) accumulation and spatial memory impairment in a mouse model of Fabry disease. |
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| Συγγραφείς: | Salluzzo M; Department of Medical and Clinical Sciences (DIMEC), University of Bologna, Italy., Flotta F; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy., Delprete C; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy., Lazzarotti V; Department of Medical and Clinical Sciences (DIMEC), University of Bologna, Italy., Formaggio F; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy., Vignoli B; Institute of Neuroscience, National Research Council, Padova Section, 35131 Padova, Italy., Campolongo L; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy., Campana G; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy., Carboni L; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy., Canossa M; Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Povo, Italy., Donadio V; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy., Liguori R; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy., Caprini M; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy. Electronic address: m.caprini@unibo.it., Rimondini R; Department of Medical and Clinical Sciences (DIMEC), University of Bologna, Italy. Electronic address: roberto.rimondini@unibo.it. |
| Πηγή: | Neurobiology of disease [Neurobiol Dis] 2026 Sep; Vol. 227, pp. 107516. Date of Electronic Publication: 2026 Jun 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE |
| Imprint Name(s): | Publication: San Diego, CA : Academic Press Original Publication: Oxford : Blackwell Science, c1994- |
| Ιατρικοί όροι (MeSH): | Fabry Disease*/metabolism , Fabry Disease*/pathology , Fabry Disease*/complications , Fabry Disease*/genetics , Trihexosylceramides*/metabolism , Hippocampus*/metabolism , Hippocampus*/pathology , Memory Disorders*/pathology , Memory Disorders*/etiology , Memory Disorders*/metabolism , Spatial Memory*/physiology, Maze Learning/physiology ; alpha-Galactosidase/genetics ; alpha-Galactosidase/metabolism ; Microglia/metabolism ; Microglia/pathology ; Astrocytes/metabolism ; Astrocytes/pathology ; Neurons/metabolism ; Neurons/pathology ; Glial Fibrillary Acidic Protein/metabolism ; Animals ; Disease Models, Animal ; Mice, Knockout ; Mice ; Mice, Inbred C57BL ; Male |
| Περίληψη: | 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. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest Authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Astrocyte; Fabry disease; Globotriaosylceramide (Gb3); Microglia; Morris water maze; Neuron; Spatial memory; α-Gal A(-/0) mouse model |
| Substance Nomenclature: | 0 (Trihexosylceramides) 71965-57-6 (globotriaosylceramide) EC 3.2.1.22 (alpha-Galactosidase) 0 (Glial Fibrillary Acidic Protein) |
| Entry Date(s): | Date Created: 20260630 Date Completed: 20260722 Latest Revision: 20260722 |
| Update Code: | 20260723 |
| DOI: | 10.1016/j.nbd.2026.107516 |
| PMID: | 42379398 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1095-953X |
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| DOI: | 10.1016/j.nbd.2026.107516 |