title: PKCε deficits in Alzheimer's disease brains and skin fibroblasts.
abstract: In Alzheimer's disease (AD) transgenic mice, activation of synaptogenic protein kinase C ε (PKCε) was found to prevent synaptotoxic amyloid-β (Aβ)-oligomer elevation, PKCε deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKCε in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKCε and Aβ in the brains of autopsy-confirmed AD patients (n = 20) and age-matched controls (AC, n = 19), and in skin fibroblast samples from AD (n = 14), non-AD dementia patients (n = 14), and AC (n = 22). Intraneuronal Aβ levels were measured immunohistochemically (using an Aβ-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKCε was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas Aβ levels were significantly higher. The ratio of PKCε to Aβ in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKCε was inversely correlated with Aβ levels in controls, whereas in AD patients, PKCε showed no significant correlation with Aβ. In autopsy brains, PKCε decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKCε compared to controls and an AD-specific change in the Aβ-oligomer effects on PKCε. Together, these data demonstrate that the relationship between Aβ levels and PKCε is markedly altered in AD patients' brains and skin fibroblasts, reflecting a loss of protective effect of PKCε against toxic Aβ accumulation. These changes of PKCε levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker.
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Khan
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Sen
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaisan
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Chol S
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nelson
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, WV, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D001344:Autopsy; D001921:Brain / Q000201:enzymology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D011493:Protein Kinase C
keywords: Alzheimer's disease; PKCε; amyloid-β oligomers; diagnostic assay; peripheral biomarker