title: Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function.
abstract: Obstructive sleep apnea (OSA) is a frequent medical condition characterized by intermittent hypoxia (IH) during sleep, and is associated with neurodegenerative changes in several brain regions along with learning deficits. We hypothesized that aging rats exposed to IH during sleep would be particularly susceptible. Young (3-4 months) and aging (20-22 months) Sprague-Dawley rats were therefore exposed to either room air or IH for 14 days. Learning and memory was assessed with a standard place-training version of the Morris water maze. Aging rats exposed to room air (RA) or IH displayed significant spatial learning impairments compared with similarly exposed young rats; furthermore, the decrements in performance between RA and IH were markedly greater in aging compared with young rats (p < 0.01), and coincided with the magnitude of IH-induced decreases in cyclic AMP response element binding (CREB) phosphorylation. Furthermore, decreases in proteasomal activity occurred in both young and aging rats exposed to IH, but were substantially greater in the latter (p < 0.001). Neuronal apoptosis, as shown by cleaved caspase 3 expression, was particularly increased in aging rats exposed to IH (p < 0.01 versus young rats exposed to IH). Collectively, these findings indicate unique vulnerability of the aging rodent brain to IH, which is reflected at least in part, by the more prominent decreases in CREB phosphorylation and a marked inability of the ubiquitin-proteasomal pathway to adequately clear degraded proteins.
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA. david.gozal@louisville.edu
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.forename: Barry W
authors.initials: BW
authors.lastname: Row
authors.forename: Leila
authors.initials: L
authors.lastname: Kheirandish
authors.forename: Rugao
authors.initials: R
authors.lastname: Liu
authors.forename: Shang Z
authors.initials: SZ
authors.lastname: Guo
authors.forename: Fan
authors.initials: F
authors.lastname: Qiang
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Brittian
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D018782:Maze Learning; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D020181:Sleep Apnea, Obstructive / Q000503:physiopathology; D013037:Spatial Behavior
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009097:Multienzyme Complexes; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex