title: Type-dependent oxidative damage in frontotemporal lobar degeneration: cortical astrocytes are targets of oxidative damage.
abstract: Oxidative injury and stress responses are common features of many neurodegenerative diseases. To assess oxidative stress responses in frontotemporal lobar degeneration (FTLD), we identified increased 4-hydroxynonenal (HNE) adducts using gel electrophoresis and Western blotting in frontal cortex samples in 6 of 6 cases of FTLD with the P301L mutation in the tau gene (FTLD-tau), in 3 of 10 cases with tau-negative ubiquitin-immunoreactive inclusions, and in 2 of 3 cases associated with motor neuron disease. Selectively increased lipoxidation-derived protein damage associated with altered membrane unsaturation and fatty acid profiles was verified by mass spectrometry in FTLD-tau and FTLD associated with motor neuron disease. All FTLD-tau and most cases with increased HNE-positive bands had marked astrocytosis as determined by glial fibrillary acidic protein (GFAP) immunohistochemistry and increased GFAP expression on Western blotting; 2 FTLD cases with tau-negative ubiquitin-immunoreactive inclusions and with increased GFAP expression did not have increased HNE adducts. Bidimensional gel electrophoresis, Western blotting, in-gel digestion, and mass spectrometry identified GFAP as a major target of lipoxidation in all positive cases; confocal microscopy revealed colocalization of HNE and GFAP in cortical astrocytes, superoxide dismutase 1 in astrocytes, and superoxide dismutase 2 in astrocytes and neurons in all FTLD types. Thus, in FTLD, there is variable disease-dependent oxidative damage that is prominent in FTLD-tau, astrocytes are targets of oxidative damage, and GFAP is a target of lipoxidation. Astrocytes are, therefore, crucial elements of oxidative stress responses in FTLD.
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martínez
authors.forename: Margarita
authors.initials: M
authors.lastname: Carmona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003704:Dementia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin; D016875:tau Proteins; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human; C027576:4-hydroxy-2-nonenal