title: Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease.
abstract: Characterization of the earliest neuropathologic features of Alzheimer disease (AD) indicates that synaptic degeneration accompanied by tau hyperphosphorylation and amyloid deposition might be an important feature. The mechanisms involved are unclear; however, dysregulation of signaling cascades such as the extracellular signal-regulated kinase (ERK) pathway might play a role. In this context, the main objective of this study was to determine whether ERK hyperactivation occurs in early stages of AD. We compared the patterns of total and phosphorylated ERK (pERK) expression in the midfrontal cortex of patients clinically and neuropathologically characterized with early, intermediate, or advanced AD. Immunocytochemical and Western blot analysis showed that in early AD, there was extensive activation of ERK in astroglial cells in the white matter accompanied by intense astrogliosis. In contrast, in patients with more advanced AD, pERK immunoreactivity was associated with neuronal cell bodies and dystrophic neurites around plaques. Levels of astroglial pERK immunoreactivity in the white matter were strongly correlated with scores of cognitive performance (Blessed, Mini-Mental Status Examination, and Clinical Dementia Rating) and with the severity of AD neuropathology (Braak stage). These findings suggest that astroglial ERK activation may be an important early response to the onset of AD pathology. Identification of cell signaling events unique to early AD may provide therapeutic targets for the prevention or delay of dementia.
authors.affiliation: Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093-0624, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Webster
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hansen
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Magdalena
authors.initials: M
authors.lastname: Torrance
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D012044:Regression Analysis
chemical_list: D015415:Biomarkers; D048049:Extracellular Signal-Regulated MAP Kinases