title: Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2.
abstract: Conditional presenilin 1 and presenilin 2 double knockout causes memory dysfunction and reproduces neurodegenerative phenotypes of Alzheimer disease (AD) in mice. Oxidative stress has been long implicated predominantly in amyloidosis-mediated AD pathologies; however, its role in response to the loss-of-function pathogenic mechanism of AD remains unclear. In this study, we examined the oxidative stress status in PS1 and PS2 double-knockout (PS cDKO) mice using F(2)-isoprostanes (iPF(2alpha)-III) as the marker of lipid peroxidation. Lipid peroxidation was enhanced in a gender- and age-related manner in the PS cDKO mice independent of brain Abeta deposition. Such oxidative abnormalities predominantly in cerebral cortex at 2-4 months of age preceded the onset of many pronounced AD neuropathologies, suggesting that increased lipid peroxidation is not only an early pathophysiological response to PS inactivation, but also a potential culprit responsible for the AD-like neurodegenerative pathologies in the PS cDKO mice. Western blot analysis of cortical glial fibrillary acidic protein demonstrated an increased astrogliosis response to PS inactivation, in particular in the PS cDKO mice at as young as 2 months of age, suggesting that lipid peroxidation and neuronal injury may be closely associated with the loss-of-function neuropathogenic mechanism of AD.
authors.affiliation: Key Laboratory of Brain Functional Genomics, Ministry of Education of China and the Science and Technology Commission of Shanghai Municipality, Shanghai Institute of Brain Functional Genomics, East China Normal University, Shanghai 200062, China.
authors.forename: Manjie
authors.initials: M
authors.lastname: Zhu
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Jianting
authors.initials: J
authors.lastname: Shi
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Hu
authors.forename: Yinghe
authors.initials: Y
authors.lastname: Hu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D002374:Catalase / Q000097:blood; D002540:Cerebral Cortex / Q000737:chemistry; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005979:Glutathione Peroxidase / Q000097:blood; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D053766:Presenilin-2 / Q000097:blood / Q000172:deficiency*; D013482:Superoxide Dismutase / Q000097:blood
chemical_list: D000975:Antioxidants; D005904:Glial Fibrillary Acidic Protein; D053766:Presenilin-2; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase