Type-Dependent Oxidative Damage 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 HNEpositive 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.

This work was supported by Grants PI05/1570 and PI05/2214 from the Spanish Ministry of Health, Instituto de Salud Carlos III, and by Grant LSHM-CT-2004-503039 from the European Commission under the Sixth Framework Program (BrainNet Europe II) to Isidre Ferrer; by Grant BFU2006-14495/BFI from the Spanish Ministry of Education and Science, by Grant RD06/0013/0012 from the Spanish Ministry of Health (ISCIII, Red de Envejecimiento y Fragilidad), and by Grant 2005SGR00101 from the Autonomous Government of Catalonia to Reinald Pamplona; and by the Spanish Ministry of Health (Grants PI04/0355, PI05/2214, and PI05/2241), Spanish Ministry of Education and Science (Grant AGL2006-12433), B La Caixa[ Foundation, and COST B-35 Action to Manuel Portero-Otin.