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Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients

Institute of Pharmacological Sciences (Drs. Govoni, Bergamaschi, and Racchi), University of Milan, Milan; the Department of Experimental Medicine and Biochemical Sciences (Drs. Battaini and Trabucchi), University of Rome, Rome; and the Alzheimer Department (Drs. Binetti, Bianchetti, and Trabucchi), Sacred Heart Hospital, Brescia, Italy.

We attempted to determine whether changes in protein kinase C (PKC) activity in Alzheimer's disease (AD) brains are also present in cultured skin fibroblasts from living patients. Biopsies collected from shoulder skin were transferred to culture plates with an appropriate growth medium, and histone-directed PKC activity as well as phorbol ester binding were individually determined in soluble and particulate fractions prepared from AD and non-AD fibroblast cell lines. Binding experiments indicated that PKC was unevenly distributed between cytosol (78%) and particulate (22%). The Bmax values for phorbol ester binding in soluble and particulate fractions were similar in AD and non-AD patients. Kd values in the cytosol were 94% higher in AD patients, indicating lower affinity of the enzyme for the ligand. Accordingly, the soluble PKC activity was 30% lower in AD patients. The data suggest that the changes in PKC phosphorylating activity represent a diffuse cellular defect in AD and are not confined to the brain. The alterations of the enzyme may participate in the disregulation in processing of ß-amyloid precursor protein in AD.

Address correspondence and reprint requests to Dr. S. Govoni, Institute of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.

Received February 9, 1993. Accepted for publication in final form May 14, 1993.

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