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(American Journal of Pathology. 1999;155:1163-1172.)
© 1999 American Society for Investigative Pathology

Regular Articles

A New Molecular Link between the Fibrillar and Granulovacuolar Lesions of Alzheimer's Disease

Nupur Ghoshal^*, John F. Smiley, Anthony J. DeMaggio, Merl F. Hoekstra, Elizabeth J. Cochran^§, Lester I. Binder^* and Jeff Kuret^¶

From the Department of Cell and Molecular Biology ^*
Institute, for Neuroscience, Northwestern University Medical School, Chicago, Illinois; the Program in Cognitive Neuroscience and Schizophrenia,
Nathan Kline Institute for Psychiatric Research, Orangeburg, New York; the ICOS Corporation,
Bothell, Washington; the Department of Neurological Sciences,^§
Rush Alzheimer's Disease Center, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; and the Department of Medical Biochemistry,^¶
Ohio State University College of Medicine, Columbus, Ohio

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder involving select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumulate hyperphosphorylated tau protein polymerized into filaments, and granulovacuolar lesions, which appear primarily within the hippocampus. The mechanism by which only select populations of neurons develop these lesions as well as the relationship between them is unknown. To address these questions, we have turned to AD tissue to search for enzymes specifically involved in tau hyperphosphorylation. Recently, we showed that the principal phosphotransferases associated with AD brain-derived tau filaments are members of the casein kinase-1 (CK1) family of protein kinases. Here we report the distribution of three CK1 isoforms (Cki, Cki, and Cki) in AD and control brains using immunohistochemistry and Western analysis. In addition to colocalizing with elements of the fibrillar pathology, CK1 is found within the matrix of granulovacuolar degeneration bodies. Furthermore, levels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Cki, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key role in the hyperphosphorylation of tau and in the formation of AD-related pathology.

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