title: Protein kinase C activity is associated with prefrontal cortical decline in aging.
abstract: Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.
authors.affiliation: Yale University School of Medicine, Department of Neurobiology, 333 Cedar Street, New Haven, CT 06511, USA. avis.brennan@yale.edu
authors.forename: Avis R
authors.initials: AR
authors.lastname: Brennan
authors.forename: Peixiong
authors.initials: P
authors.lastname: Yuan
authors.forename: Dara L
authors.initials: DL
authors.lastname: Dickstein
authors.forename: Anne B
authors.initials: AB
authors.lastname: Rocher
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Husseini
authors.initials: H
authors.lastname: Manji
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001284:Atrophy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053119:Benzophenanthridines / Q000494:pharmacology; D003072:Cognition Disorders / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000201:enzymology / Q000473:pathology; D049229:Dendritic Spines / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; C016299:chelerythrine; D011493:Protein Kinase C