A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease. Am J Pathol 1999 Oct;155(4):1163-72
Date
10/09/1999Pubmed ID
10514399Pubmed Central ID
PMC1867028DOI
10.1016/S0002-9440(10)65219-4Scopus ID
2-s2.0-0032870947 (requires institutional sign-in at Scopus site) 129 CitationsAbstract
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 (Ckialpha, Ckidelta, and Ckiepsilon) 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, Ckidelta, 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.
Author List
Ghoshal N, Smiley JF, DeMaggio AJ, Hoekstra MF, Cochran EJ, Binder LI, Kuret JAuthor
Elizabeth J. Cochran MD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAged, 80 and over
Alkaline Phosphatase
Alzheimer Disease
Antibodies, Monoclonal
Antibody Specificity
Blotting, Western
Brain
Casein Kinases
Cytoplasmic Granules
Female
Humans
Immunohistochemistry
Isoenzymes
Male
Middle Aged
Neurofibrillary Tangles
Phosphorylation
Protein Kinases
Vacuoles
tau Proteins
