I2-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

• Published in: Neurobiology of aging 2012-12, Vol.33 (12), p.2807-2816
• Main Authors: Murray, Patrick, Kirkwood, Caitlin, Gray, Megan, Ikonomovic, Milos, Paljug, William, Abrahamson, Eric, Henteleff, Ruth, Hamilton, Ronald, Kofler, Julia, Klunk, William, Lopez, Oscar, Penzes, Peter, Sweet, Robert
• Format: Article
• Language: English
• Subjects: Aging
• ISSN: 0197-4580
• DOI: 10.1016/j.neurobiolaging.2012.02.015

Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble I2-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble I2-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the I2-amyloid1a42/I2-amyloid1a40 ratio was increased, due primarily to reduced soluble I2-amyloid1a40, and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical I2-amyloid1a42/I2-amyloid1a40 ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.