A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder involv ing select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumu late hyperphosphorylated tau protein polymerized into filaments, and granul ovacuolar lesions, which appear primarily within the hippocampus. The mecha nism by which only select populations of neurons develop these lesions as w ell as the relationship between them is unknown. To address these questions , we have turned to AD tissue to search for enzymes specifically involved i n tau hyperphosphorylation. Recently, we showed that the principal phosphot ransferases associated with AD brain-derived tau filaments are members of t he casein kinase-1 (CK1) family of protein kinases, Here we report the dist ribution of three CK1 isoforms (Cki alpha, Cki delta, and Cki epsilon) in A D and control brains using immunohistochemistry and Western analysis. In ad dition to colocalizing with elements of the fibrillar pathology, CK1 is fou nd within the matrix of granulovacuolar degeneration bodies. Furthermore, l evels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Cki delta, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key r ole in the hyperphosphorylation of tau and in the formation of AD-related p athology.